Patent Publication Number: US-2022227830-A1

Title: Qd dosing of gip receptor agonist peptide compounds and uses thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a by-pass continuation application under 35 U.S.C. § 111(a) of PCT Application No. PCT/JP2021/014423, filed on Mar. 25, 2021, which claims priority to U.S. Provisional Application Ser. No. 62/994,716, filed on Mar. 25, 2020, the entire contents of which are incorporated by reference herein. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to a novel peptide compound having an activating action on GIP receptors and use of the peptide compound as a medicament which may be dosed in a once daily dosing regimen. 
     BACKGROUND 
     The statements in this section merely provide background information related to the present disclosure and may not constitute prior art. 
     Both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptides called incretin. GLP-1 and GIP are secreted from small intestinal L cells and K cells, respectively. 
     GLP-1 acts via GLP-1 receptors and is known to have a glucose-dependent insulinotropic action and a feeding suppressive action. On the other hand, GIP is known to have a glucose-dependent insulinotropic action via the GIP receptors (GIPr), though an influence of GIP only on feeding is not clear. 
     Attempts have been made to search for peptides having GLP-1 receptor/GIP receptor coagonist or glucagon receptor/GLP-1 receptor/GIP receptor triagonist activity and modifications thereof and develop these peptides as anti-obesity drugs, therapeutic drugs for diabetes, or therapeutic drugs for neurodegenerative disorders based on the structure of natural glucagon, GIP, or GLP-1. However, the peptide compound and the compound having a selective activating action on GIP receptors of the present disclosure for the use in treating emesis and similar symptoms associated with nausea and vomiting have not been disclosed. 
     Patients who experience nausea and vomiting are often unwilling or unable to take their medication regularly; several studies have shown that a less frequent dosing results in higher degree of compliance and thus eventually better treatment of the patients. Therefore, there is an unmet need for long acting preparations of antiemetic medicine. In particular there is a need for long acting preparations of antiemetic GIP receptor agonist peptides that represent an alternative to twice per day (BID) dosing formulations in order to make a change in dosing regimen, frequency of medication or type of medication, more flexible. Extending the duration of action will also provide benefit in diseases where the duration of emetic episodes is longer. 
     All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety. 
     SUMMARY 
     It is an object of the present invention to provide a GIP receptor agonist peptide compound which has a GIP receptor activation action and is useful as a preventive/therapeutic agent for diabetes, obesity, and/or an antiemetic agent to prevent/treat diseases accompanied by vomiting or nausea. 
     The present disclosure provides GIPr agonist peptide compounds comprising a sequence represented by formulae (I)-(V) that are useful as therapeutic agents for the prevention or treatment of emesis as described herein. Surprisingly, the compounds of formulae (I)-(V) exhibit excellent GIP receptor activation action, a longer ½ life of elimination and improved solubility. Unexpectedly, in some instances, the peptides of formulae (I)-(V) relative to other known GIPr agonist peptides in the art possess improved properties in one or more of: (1) stability in serum, (2) half-life of elimination and (3) solubility. In certain embodiments of this disclosure, the peptides of formulae (I)-(V) relative to other known GIPr agonist peptides that are dosed once per day to treat emesis, or which may be useful as preventative agents of nausea and/or vomiting and other symptoms of emesis, possess improved properties in one or more of: (1) stability in serum, (2) half-life of elimination and (3) solubility. 
     More specifically, the present disclosure includes the following embodiments: 
     Embodiment (1). A GIP receptor agonist peptide represented by formula (I): P 1 -Tyr-A2-Glu-Gly-Thr-Phe-Ile-Ser-A9-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-A24-Trp-A26-Leu-A28-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 , or a pharmaceutically acceptable salt thereof; 
     wherein
 
P 1  represents a group represented by formula
 
     —R A1 , 
     —CO—R A1 , 
     —CO—OR A1 , 
     —CO—COR A1 , 
     —SO—R A1 , 
     —SO 2 —R A1 ,
 
—SO 2 —OR A1 ,
 
—CO—NR A2 R A3 ,
 
—SO 2 —NR A2 R A3 ,
 
—C(═NR A1 )—NR A2 R A3 , or
 
is absent,
 
wherein R A1 , R A2 , and R A3  each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
 
P 2  represents —NH 2  or —OH;
 
A2: represents Aib, D-Ala, Ala, Gly, or Pro;
 
A9: represents Asp or Leu;
 
A13: represents Aib, or Ala;
 
A14: represents Leu, Aib, Lys;
 
A16: represents Arg, Ser, or Lys;
 
A17: represents Aib, Gln, or Ile;
 
A18: represents Ala, His, or Lys;
 
A19: represents Gln, or Ala;
 
A20: represents Aib, Gln, Lys, or Ala;
 
A21: represents Asp, Asn, or Lys;
 
A24: represents Asn, or Glu;
 
A26: represents Leu or Lys;
 
A28: represents Ala, Lys, or Aib;
 
A29: represents Gln, Lys, Gly, or Aib;
 
A30: represents Arg, Gly, Ser, or Lys;
 
A31: represents Gly, Pro, or a deletion;
 
A32: represents Ser, Gly, or a deletion;
 
A33: represents Ser, Gly, or a deletion;
 
A34: represents Gly, Lys, Asn, or a deletion;
 
A35: represents Ala, Asp, Ser, Lys, or a deletion;
 
A36: represents Pro, Trp, Lys, or a deletion;
 
A37: represents Pro, Lys, Gly, or a deletion;
 
A38: represents Pro, His, Lys, or a deletion;
 
A39: represents Ser, Asn, Gly, Lys, or a deletion; and
 
A40: represents Ile, Lys or a deletion.
 
     Embodiment (2). A GIP receptor agonist peptide, represented by formula (II): P 1 -Tyr-A2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-A19-A20-A21-Phe-Val-A24-Trp-A26-Leu-Ala-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 , or a pharmaceutically acceptable salt thereof, wherein: 
     P 1  represents a group represented by formula 
     —R A1 , 
     —CO—R A1 , 
     —CO—OR A1 , 
     —CO—COR A1 , 
     —SO—R A1 , 
     —SO 2 —R A1 ,
 
—SO 2 —OR A1 ,
 
—CO—NR A2 R A3 ,
 
—SO 2 —NR A2 R A3 , or
 
—C(═NR A1 )—NR A2 R A3  
 
wherein R A1 , R A2 , and R A3  each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
 
P 2  represents —NH 2  or —OH;
 
A2: represents Aib, Ser, Ala, D-Ala, or Gly;
 
A13: represents Aib, Tyr, or Ala;
 
A14: represents Leu, or Lys(R);
 
A16: represents Arg, Ser, or Lys;
 
A17: represents Aib, Ile, Gln, or Lys(R);
 
A18: represents Ala, His, or Lys(R);
 
A19: represents Gln or Ala;
 
A20: represents Aib, Gln, or Lys(R);
 
A21: represents Asn, Glu, Asp, or Lys(R);
 
A24: represents Asn, or Glu;
 
A26: represents Leu or Lys(R);
 
A28: represents Ala, Aib, or Lys(R);
 
A29: represents Gln, Aib, or Lys(R)
 
A30: represents Arg, Gly, Lys, Ser, or Lys(R);
 
A31: represents Gly, Pro, or a deletion;
 
A32: represents Ser, Lys, Pro, Gly, or a deletion;
 
A33: represents Ser, Lys, Gly, or a deletion;
 
A34: represents Gly, Lys, Asn, or a deletion;
 
A35: represents Ala, Asp, Ser, Lys, or a deletion;
 
A36: represents Pro, Trp, Lys, or a deletion;
 
A37: represents Pro, Lys, Gly, or a deletion;
 
A38: represents Pro, His, Lys, or a deletion;
 
A39: represents Ser, Asn, Lys, Gly, or a deletion;
 
A40: represents Ile, Lys(R), or a deletion;
 
wherein in the residue Lys(R), the (R) portion represents X-L-, wherein L represents a linker, and is selected from the following group consisting of gE, GGGGG, GGEEE, G2E3, G3gEgE, 2OEGgEgE, OEGgEgE, GGPAPAP, 2OEGgE, 3OEGgEgE, G4gE, G5gE, 2OEGgEgEgE, 2OEG and G5gEgE; and X represents a lipid.
 
     Embodiment (3). A GIP receptor agonist peptide represented by formula (IV): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-Asn-Trp-Leu-Leu-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P 2 , or a pharmaceutically acceptable salt thereof; 
     Wherein 
     P 1  represents H, C 1-6  alkyl, or absent;
 
P 2  represents —NH 2  or —OH;
 
A2 represents Aib, Gly, or Ser;
 
A6 represents Phe or Leu;
 
A7 represents Ile or Thr;
 
A13 represents Ala, Aib, or Tyr;
 
A14 represents Leu, Lys, or Lys(R);
 
A16 represents Lys, Arg, or Ser;
 
A17 represents Aib, Ile, Lys, or Lys(R);
 
A18 represents Ala, His, Lys, or Lys(R);
 
A20 represents Gln, Lys, Lys(R), or Aib;
 
A21 represents Asp, Lys, Lys(R), or Asn;
 
A28 represents Ala, Aib, or, Lys, Lys(R);
 
A29 represents Gln, Lys, Lys(R), or Aib;
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac);
 
A31 represents Pro, Gly, or a deletion;
 
A32 represents Ser, Gly, or a deletion;
 
A33 represents Ser, Gly, or a deletion;
 
A34 represents Gly, Lys, or a deletion;
 
A35 represents Ala, Ser, Lys, or a deletion;
 
A36 represents Pro, Lys, or a deletion;
 
A37 represents Pro, Lys, Gly, or a deletion;
 
A38 represents Pro, Lys, or a deletion; and
 
A39 represents Ser, Gly, Lys, or a deletion,
 
wherein in the residue Lys(R), the (R) portion represents X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE; and X represents C 14 -C 18  monoacid or C 14 -C 18  diacid.
 
     Embodiment (4). The GIP receptor agonist peptide according to embodiment (3) or the pharmaceutically acceptable salt thereof, wherein 
     A14 represents Leu or Lys(R);
 
A17 represents Aib, Ile, or Lys(R);
 
A18 represents Ala, His, or Lys(R);
 
A20 represents Gln, Lys(R), or Aib;
 
A21 represents Asp, Lys(R), or Asn;
 
A28 represents Ala, Aib, or Lys(R);
 
A29 represents Gln, Lys(R), or Aib, and
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac).
 
     Embodiment (5). The GIP receptor agonist peptide or the pharmaceutically acceptable salt thereof according to embodiment (4) has a solubility of at least 15 mg/mL in phosphate buffer at pH 7.4. 
     Embodiment (6). The GIP receptor agonist peptide according to embodiment (3) or the pharmaceutically acceptable salt thereof, wherein 
     A2 represents Aib;
 
A17 represents Aib, Lys, or Lys(R);
 
A20 represents Aib; and
 
A28 represents Ala or Aib,
 
wherein L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3, G4gE, G4gEgE, G5, G5E, G5gE, G5gEgE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE.
 
     Embodiment (7). The GIP receptor agonist peptide according to embodiment (6) or the pharmaceutically acceptable salt thereof, wherein 
     A14 represents Leu or Lys(R);
 
A17 represents Aib or Lys(R).
 
A18 represents Ala, His, or Lys(R);
 
A21 represents Asp, Lys(R), or Asn;
 
A29 represents Gln, Lys(R), or Aib; and
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac).
 
     Embodiment (8). The GIP receptor agonist peptide or the pharmaceutically acceptable salt thereof according to embodiment (7) has a solubility of at least 30 mg/mL in phosphate buffer at pH 7.4. 
     Embodiment (9). The GIP receptor agonist peptide according to any one of embodiments (1)-(8) or the pharmaceutically acceptable salt thereof, wherein A31 is Gly, and A32-A39 are deletion; or A32 is Gly and 33-A39 are deletion. 
     Embodiment (10). The GIP receptor agonist peptide according to any one of embodiments (1)-(9) or the pharmaceutically acceptable salt thereof, wherein P 2  is —OH. 
     Embodiment (11). The GIP receptor agonist peptide according to any one of embodiments (2)-(10) or the pharmaceutically acceptable salt thereof, wherein Lys(R) is a Lys residue, and wherein the side chain of said Lys residue is substituted with (R). 
     Embodiment (12). The GIP receptor agonist peptide according to embodiment (11) or the pharmaceutically acceptable salt thereof, wherein Lys(R) is a Lys residue substituted with (R), and (R) is represented by X-L-, wherein L is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 3OEGgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE. 
     Embodiment (13). The GIP receptor agonist peptide according to embodiment (12) or the pharmaceutically acceptable salt thereof, wherein L is selected from 2OEGgEgE, OEGgEgE, 2OEGgE, GGGGG, G5gEgE, 2OEG and G5gEgE; and X is a C 14 -C 16  monoacid or diacid group or X is a C 15 -C 18  diacid. 
     Embodiment (14). The GIP receptor agonist peptide according to embodiment (13) or the pharmaceutically acceptable salt thereof, wherein L is 2OEGgEgE or GGGGG. 
     Embodiment (15). The GIP receptor agonist peptide according to embodiment (13) or the pharmaceutically acceptable salt thereof, wherein X is C 15  diacid or C 16  diacid. 
     Embodiment (16). The GIP receptor agonist peptide according to embodiment (15) or the pharmaceutically acceptable salt thereof, wherein X is C 15  diacid. 
     Embodiment (17). The GIP receptor agonist peptide according to embodiment (13) or the pharmaceutically acceptable salt thereof, wherein the linker (L) is 2OEGgEgE or GGGGG, and (R) is 2OEGgEgE-C 15  diacid or (R) is 2OEGgEgE-C 16  diacid. 
     Embodiment (18). The GIPR agonist peptide according to any one of embodiments (2)-(15) or the pharmaceutically acceptable salt thereof, represented by formula (V): P 1 -Tyr-Aib-Glu-Gly-The-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-Leu-Asp-Arg-Aib-A18-Gln-Aib-A21-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-A30-A31-A32-P 2 , wherein 
     P 1  is methyl;
 
P 2  is OH or NH 2 ;
 
A13 represents Ala or Aib;
 
A18 represents Ala, Lys, or Lys(R);
 
A21 represents Lys, Lys(R), or Asp;
 
A30 represents Lys or Ser;
 
A31 represents Gly or Pro; and
 
A32 represents Gly or deletion;
 
wherein (R) represents X-L-, L represents 2OEGgEgE or GGGGG; and X represents a C 15  diacid or C 16  diacid.
 
     Embodiment (19). The GIPR agonist peptide of embodiment (18) or the pharmaceutically acceptable salt thereof, wherein 
     A18 represents Ala or Lys(R); and
 
A21 represents Lys(R) or Asp.
 
     Embodiment (20). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R-Aib-A-Q-Aib-Km-F-V-N-W-L-L-A-Q-R-P 2 ; wherein Km is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (21). The GIP receptor agonist peptide according to embodiment (20), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-NH2; wherein Lys(R) is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (22). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R-Aib-Km-Q-Aib-N-F-V-N-W-L-L-A-Q-S-P-S-S-G-A-P-P-P-S-P 2 ; wherein Km is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (23). The GIP receptor agonist peptide according to any one of embodiments (2)-(19), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R-Aib-A-Q-Aib-Km-F-V-N-W-L-L-A-Q-K-G-P 2 ; 
     wherein Km is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (24). The GIPR agonist peptide of embodiment (23) or the pharmaceutically acceptable salt thereof, represented by the formula: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-OH; wherein Lys(R) is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (25). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-Km-D-R-Aib-A-Q-Aib-D-F-V-N-W-L-L-A-Q-R-G-P 2 ; wherein Km is Lys-GGGGG-C 15  diacid. 
     Embodiment (26). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-L-D-R-Aib-A-Q-Aib-N-F-V-N-W-L-L-A-Q-Km-P-S-S-G-A-P-P-P-S-P 2 ; wherein Km is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (27). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-Km-D-R-Aib-A-Q-Aib-N-F-V-N-W-L-L-A-Q-S-P-S-S-G-A-P-P-P-S-P 2 ; wherein Km is Lys-GGGGG-C 15  diacid. 
     Embodiment (28). The GIP receptor agonist peptide according to any one of embodiments (2)-(5), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-L-D-R-Km-A-Q-Aib-N-F-V-N-W-L-L-A-Q-R-P-S-S-G-A-P-P-P-S-P 2 ; wherein Km is Lys-2OEGgEgE-C 15  diacid. 
     Embodiment (29). The GIP receptor agonist peptide according to any one of embodiments (2)-(19) or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R-Aib-A-Q-Aib-Km-F-V-N-W-L-L-A-Q-K-G-P 2 ; wherein Km is Lys-2OEGgEgE-C 16  diacid. 
     Embodiment (30). The GIPR agonist peptide of embodiment (29), or the pharmaceutically acceptable salt thereof, represented by the formula: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-OH; wherein Lys(R) is Lys-2OEGgEgE-C 16  diacid. 
     Embodiment (31). The GIP receptor agonist peptide according to any one of embodiments (2)-(19), or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: P 1 -Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-L-D-R-Aib-Km-Q-Aib-D-F-V-N-W-L-L-A-Q-S-P-G-P 2 ; wherein Km is Lys-2OEGgEgE-C 16  diacid. 
     Embodiment (32). The GIPR agonist peptide of embodiment (31) or the pharmaceutically acceptable salt thereof, represented by the formula: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Lys(R)-Gln-Aib-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Ser-Pro-Gly-OH; wherein Lys(R) is Lys-2OEGgEgE-C 16  diacid. 
     Embodiment (33). The GIP receptor agonist peptide according to any one of embodiments (2)-(8) or the pharmaceutically acceptable salt thereof, wherein the amino acid sequence comprises: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(R)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Ser-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH; wherein Lys(R) is Lys-GGGGG-C 15  diacid. 
     Embodiment (34). The GIP receptor agonist peptide according to any one of embodiments (1)-(19), wherein P 1  is Methyl- (Me) and P 2  is —OH, or NH 2 . 
     Embodiment (35). The GIP receptor agonist peptide according to any one of embodiments (1)-(34), wherein the GIP receptor agonist peptide has a selectivity ratio, expressed as a ratio of (GLP1R EC 50 /GIPR EC 50 ) of greater than 10, or greater than 100, or greater than 1,000, or greater than 100,000. 
     Embodiment (36). A medicament comprising the GIP receptor agonist peptide according to any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof. 
     Embodiment (37). A pharmaceutical composition comprising the GIP receptor agonist peptide according to any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof. 
     Embodiment (38). The GIP receptor agonist peptide or the salt thereof according to any one of embodiments (1)-(35), or the medicament according to embodiment (36), or the pharmaceutical composition according to embodiment (37), which is administered once per day (QD), or once every 24 hrs to alleviate or treat emesis as a monotherapy or as an adjunct therapy. 
     Embodiment (39). Use of the GIP receptor agonist peptide according to any one of embodiments (1)-(35) or a salt thereof, or the medicament according to embodiment (36), or the pharmaceutical composition according to embodiment (37), for the manufacture of a suppressant for vomiting or nausea. 
     Embodiment (40). The peptide of according to any one of embodiments (1)-(35), or a salt thereof, or the medicament according to embodiment (36), or the pharmaceutical composition according to embodiment (37), for use in suppressing vomiting or nausea. 
     Embodiment (41). A method for preventing or treating emesis in a subject, comprising administering an effective amount of the peptide according to any one of embodiments (1)-(35), or a salt thereof, or the medicament according to embodiment (36), or the pharmaceutical composition according to embodiment (37), to the subject. 
     Embodiment (42). The medicament according to embodiment (36), the use according to embodiment (39), the peptide or a salt thereof, the medicament, or the pharmaceutical composition according to embodiment (40), the method according to embodiment (41), wherein the emesis, vomiting or the nausea is caused by one or more conditions or causes selected from the following (1) to (10): 
     (1) Diseases accompanied by vomiting or nausea such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, chronic intestinal pseudo-obstruction, functional dyspepsia, cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hepatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness);
 
(2) Vomiting and/or nausea induced by chemotherapeutic drugs such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome;
 
(3) Vomiting or nausea caused by radiation sickness or radiation therapy for the chest, the abdomen, or the like used to treat cancers;
 
(4) Vomiting or nausea caused by a poisonous substance or a toxin;
 
(5) Vomiting and nausea caused by pregnancy including hyperemesis gravidarium; and
 
(6) Vomiting and nausea cexaused by a vestibular disorder such as motion sickness or dizziness
 
(7) Opioid withdrawal;
 
(8) Vomiting and nausea caused by post-operative nausea and vomiting;
 
(9) A vestibular disorder such as motion sickness or dizziness; and
 
(10) A physical injury causing local, systemic, acute or chronic pain.
 
     Embodiment (43). The method according to embodiment (41), wherein emesis is treated in a subject not taking a medicament to control a metabolic syndrome disorder. 
     Embodiment (44). A GIP receptor agonist peptide of any one of embodiments (1)-(35) or a salt thereof, wherein the peptide selectively activates the GIP receptor and demonstrates an antiemetic action in vivo, and wherein the antiemetic action is achieved by dosing the peptide to a subject in need thereof, once per day, or once per 24 hours. 
     It should be understood that this disclosure is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which is defined solely by the claims. Other features and advantages of the disclosure will be apparent from the following Detailed Description, the drawings, and the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIGS. 1A-1H . Exemplary GIP receptor agonist peptides of the present disclosure which are represented by any one of formulas (I)-(V). 
         FIG. 2 . Effect of Compound 14 on PYY (T-481, 10 μg/kg, s.c.) induced vomiting in dogs. 
         FIG. 3 . Effect of Compound 25, Compound 48, Compound 58, and Compound 260 on PYY (T-481, 10 μg/kg, s.c.) induced vomiting in dogs. 
         FIGS. 4A-4C . Effect of Compound 25 on morphine (0.6 mg/kg, s.c.)-induced emesis in ferrets. 
         FIGS. 5A-5C . Effect of Compound 14 on morphine (0.6 mg/kg, s.c.)-induced emesis in ferrets. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition. 
     In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. 
     In the present specification, examples of the “C 1-6  alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkyl group” include a C 1-6  alkyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl. 
     In the present specification, examples of the “C 2-6  alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl. 
     In the present specification, examples of the “C 2-6  alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl. 
     In the present specification, examples of the “C 3-10  cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl. 
     In the present specification, examples of the “optionally halogenated C 3-10  cycloalkyl group” include a C 3-10  cycloalkyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 
     In the present specification, examples of the “C 3-10  cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. 
     In the present specification, examples of the “C 6-14  aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl. 
     In the present specification, examples of the “C 7-16  aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl. 
     In the present specification, examples of the “C 1-6  alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkoxy group” include a C 1-6  alkoxy group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. 
     In the present specification, examples of the “C 3-10  cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. 
     In the present specification, examples of the “C 1-6  alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkylthio group” include a C 1-6  alkylthio group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio. 
     In the present specification, examples of the “C 1-6  alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkyl-carbonyl group” include a C 1-6  alkyl-carbonyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl. 
     In the present specification, examples of the “C 1-6  alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. 
     In the present specification, examples of the “C 6-14  aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl. 
     In the present specification, examples of the “C 7-16  aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl. 
     In the present specification, examples of the “5- to 14-membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl. 
     In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl. 
     In the present specification, examples of the “mono- or di-C 1-6  alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl. 
     In the present specification, examples of the “mono- or di-C 7-16  aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl. 
     In the present specification, examples of the “C 1-6  alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkylsulfonyl group” include a C 1-6  alkylsulfonyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl. 
     In the present specification, examples of the “C 6-14  arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl. 
     In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group. 
     In the present specification, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-10  cycloalkyl group, a C 3-10  cycloalkenyl group, a C 6-14  aryl group and a C 7-16  aralkyl group. 
     In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following substituent group A. 
     [Substituent Group A] 
     (1) a halogen atom,
 
(2) a nitro group,
 
(3) a cyano group,
 
(4) an oxo group,
 
(5) a hydroxy group,
 
(6) an optionally halogenated C 1-6  alkoxy group,
 
(7) a C 6-14  aryloxy group (e.g., phenoxy, naphthoxy),
 
(8) a C 7-16  aralkyloxy group (e.g., benzyloxy),
 
(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy),
 
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy),
 
(11) a C 1-6  alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),
 
(12) a C 6-14  aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
 
(13) a C 1-6  alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
 
(14) a mono- or di-C 1-6  alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
 
(15) a C 6-14  aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),
 
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy),
 
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),
 
(18) an optionally halogenated C 1-6  alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),
 
(19) a C 6-14  arylsulfonyloxy group optionally substituted by a C 1-6  alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),
 
(20) an optionally halogenated C 1-6  alkylthio group,
 
(21) a 5- to 14-membered aromatic heterocyclic group,
 
(22) a 3- to 14-membered non-aromatic heterocyclic group,
 
(23) a formyl group,
 
(24) a carboxy group,
 
(25) an optionally halogenated C 1-6  alkyl-carbonyl group,
 
(26) a C 6-14  aryl-carbonyl group,
 
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
 
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
 
(29) a C 1-6  alkoxy-carbonyl group,
 
(30) a C 6-14  aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
 
(31) a C 7-16  aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl),
 
(32) a carbamoyl group,
 
(33) a thiocarbamoyl group,
 
(34) a mono- or di-C 1-6  alkyl-carbamoyl group,
 
(35) a C 6-14  aryl-carbamoyl group (e.g., phenylcarbamoyl),
 
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl),
 
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),
 
(38) an optionally halogenated C 1-6  alkylsulfonyl group,
 
(39) a C 6-14  arylsulfonyl group,
 
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl),
 
(41) an optionally halogenated C 1-6  alkylsulfinyl group,
 
(42) a C 6-14  arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
 
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl),
 
(44) an amino group,
 
(45) a mono- or di-C 1-6  alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),
 
(46) a mono- or di-C 6-14  arylamino group (e.g., phenylamino),
 
(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino),
 
(48) a C 7-16  aralkylamino group (e.g., benzylamino),
 
(49) a formylamino group,
 
(50) a C 1-6  alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino),
 
(51) a (C 1-6  alkyl)(C 1-6  alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino),
 
(52) a C 6-14  aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino),
 
(53) a C 1-6  alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
 
(54) a C 7-16  aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino),
 
(55) a C 1-6  alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino),
 
(56) a C 6-14  arylsulfonylamino group optionally substituted by a C 1-6  alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),
 
(57) an optionally halogenated C 1-6  alkyl group,
 
(58) a C 2-6  alkenyl group,
 
(59) a C 2-6  alkynyl group,
 
(60) a C 3-10  cycloalkyl group,
 
(61) a C 3-10  cycloalkenyl group and
 
(62) a C 6-14  aryl group.
 
     The number of the above-mentioned substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, or 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. 
     In the present specification, examples of the “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     In the present specification, examples of the “aromatic heterocyclic group” (including “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (or 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     Examples of the “aromatic heterocyclic group” include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (e.g., bi or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. 
     In the present specification, examples of the “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (or 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     Examples of the “non-aromatic heterocyclic group” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and 9- to 14-membered fused polycyclic (e.g., bi or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like. 
     In the present specification, examples of the “7- to 10-membered bridged heterocyclic group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. 
     In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom. 
     In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the aforementioned substituent group A. 
     The number of the substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. 
     In the present specification, examples of the “acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 3-10  cycloalkenyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1-6  alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”. 
     Examples of the “acyl group” (also referred to as “Ac”) also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group. 
     In some embodiments, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group. 
     Examples of the “acyl group” include a formyl group, a carboxy group, a C 1-6  alkyl-carbonyl group, a C 2-6  alkenyl-carbonyl group (e.g., crotonoyl), a C 3-10  cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C 3-10  cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a C 6-14  aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C 7-16  aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 2-6  alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3-10  cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C 6-14  aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C 7-16  aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C 1-6  alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C 2-6  alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C 3-10  cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C 6-14  aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C 7-16  aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfino group, a C 1-6  alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C 1-6  alkylsulfonyl group, a C 6-14  arylsulfonyl group, a phosphono group and a mono- or di-C 1-6  alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono). 
     In the present specification, examples of the “optionally substituted amino group” include an amino group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 7-16  aralkyl-carbamoyl group, a C 1-6  alkylsulfonyl group and a C 6-14  arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6  alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C 2-6  alkenylamino group (e.g., diallylamino), a mono- or di-C 3-10  cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C 6-14  arylamino group (e.g., phenylamino), a mono- or di-C 7-16  aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C 1-6  alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-C 6-14  aryl-carbonylamino group (e.g., benzoylamino), a mono- or di-C 7-16  aralkyl-carbonylamino group (e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a mono- or di-C 1-6  alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C 1-6  alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), a (mono- or di-C 7-16  aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), a C 1-6  alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C 6-14  arylsulfonylamino group (e.g., phenylsulfonylamino), a (C 1-6  alkyl)(C 1-6  alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a (C 1-6  alkyl)(C 6-14  aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino). 
     In the present specification, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 2-6  alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3-10  cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C 6-14  aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C 7-16  aralkyl-carbamoyl group, a mono- or di-C 1-6  alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C 6-14  aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl). 
     In the present specification, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1-6  alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C 2-6  alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C 3-10  cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C 6-14  aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C 7-16  aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C 1-6  alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C 6-14  aryl-carbonyl-thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl). 
     In the present specification, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6  alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C 2-6  alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C 3-10  cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C 6-14  aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono- or di-C 7-16  aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C 1-6  alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di-C 6-14  aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl). 
     In the present specification, examples of the “optionally substituted hydroxy group” include a hydroxyl group optionally having “a substituent selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 7-16  aralkyl-carbamoyl group, a C 1-6  alkylsulfonyl group and a C 6-14  arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6  alkoxy group, a C 2-6  alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C 3-10  cycloalkyloxy group (e.g., cyclohexyloxy), a C 6-14  aryloxy group (e.g., phenoxy, naphthyloxy), a C 7-16  aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C 1-6  alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C 6-14  aryl-carbonyloxy group (e.g., benzoyloxy), a C 7-16  aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a C 1-6  alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C 1-6  alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C 7-16  aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C 1-6  alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C 6-14  arylsulfonyloxy group (e.g., phenylsulfonyloxy). 
     In the present specification, examples of the “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A” and a halogenated sulfanyl group. 
     Examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6  alkylthio group, a C 2-6  alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C 3-10  cycloalkylthio group (e.g., cyclohexylthio), a C 6-14  arylthio group (e.g., phenylthio, naphthylthio), a C 7-16  aralkylthio group (e.g., benzylthio, phenethylthio), a C 1-6  alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C 6-14  aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio). 
     In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group and a C 7-16  aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”. 
     Examples of the optionally substituted silyl group include a tri-C 1-6  alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl). 
     For descriptions of amino acid residues, the following conventions may be exemplified: Asp=D=Aspartic Acid; Ala=A=Alanine; Arg=R=Arginine; Asn=N=Asparagine; Cys=C=Cysteine; Gly=G=Glycine; Glu=E=Glutamic Acid; Gln=Q=Glutamine; His=H=Histidine; Ile=I=Isoleucine; Leu=L=Leucine; Lys=K=Lysine; Met=M=Methionine; Phe=F=Phenylalanine; Pro=P=Proline; Ser=S=Serine; Thr=T=Threonine; Trp=W=Tryptophan; Tyr=Y=Tyrosine; and Val=V=Valine. 
     Also for convenience, and readily known to one skilled in the art, the following abbreviations or symbols are used to represent the moieties, reagents and the like used in present disclosure: 
     Aib is alpha-aminoisobutyric acid; 
     mono-halo Phe—mono-halo phenylalanine; 
     bis-halo Phe—bis-halo phenylalanine; 
     mono-halo Tyr—mono-halo tyrosine; 
     bis-halo Tyr—bis-halo Tyrosine; 
     (D)-Tyr—D-tyrosine; 
     (D)-Ala—D-Alanine 
     DesNH 2 -Tyr—desaminotyrosine; 
     (D)-Phe—D-phenylalanine; 
     DesNH 2 -Phe—desaminophenylalanine; 
     (D)-Trp—D-tryptophan; 
     (D) 3 Pya—D-3-pyridylalanine; 
     2-Cl-(D)Phe—D-2-chlorophenylalanine; 
     3-Cl-(D)Phe—D-3-chlorophenylalanine; 
     4-Cl-(D)Phe—D-4-chlorophenylalanine; 
     2-F-(D)Phe—D-2-fluorophenylalanine; 
     3-F(D)Phe—D-3-fluorophenylalanine; 
     3,5-DiF-(D)Phe—D-3,5-difluorophenylalanine; 
     3,4,5-TriF-(D)Phe—D-3,4,5-trifluorophenylalanine; 
     D-Iva—D-Isovaline 
     SSA—succinimidyl succinamide; 
     PEG—polyethylene glycol; 
     PEG m —(methoxy)polyethylene glycol; 
     PEG m (12,000)—(methoxy)polyethylene glycol having a molecular weight of about 12 kD; 
     PEG m (20,000)—(methoxy)polyethylene glycol having a molecular weight of about 20 kD; 
     PEG m (30,000)—(methoxy)polyethylene glycol having a molecular weight of about 30 kD; 
     Fmoc—9-fluorenylmethyloxycarbonyl; 
     DMF—dimethylformamide; 
     DIPEA—N,N-diisopropylethylamine; 
     TFA—trifluoroacetic acid; 
     HOBT—N-hydroxybenzotriazole; 
     BOP—benzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate; 
     HBTU—2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; 
     NMP—N-methyl-pyrrolidone; 
     FAB-MS fast atom bombardment mass spectrometry; 
     ES-MS—electro spray mass spectrometry. 
     Abu: α-aminobutyric acid; 
     Acc: 1-amino-1-cyclo(C 3 -C 9 )alkyl carboxylic acid; 
     A3c: 1-amino-1-cyclopropane carboxylic acid; 
     A4c: 1-amino-1-cyclobutanecarboxylic acid; 
     A5c: 1-amino-1-cyclopentanecarboxylic acid; 
     A6c: 1-amino-1-cyclohexanecarboxylic acid; 
     Act: 4-amino-4-carboxytetrahydropyran; 
     Ado: 12-aminododecanoic acid; 
     Aib: alpha-aminoisobutyric acid; 
     Aic: 2-aminoindan-2-carboxylic acid; 
     β-Ala: beta-alanine; 
     Amp: 4-amino-phenylalanine; 
     Apc: 4-amino-4-carboxypiperidine; 
     hArg: homoarginine; 
     Aun: 11-aminoundecanoic acid; 
     Ava: 5-aminovaleric acid; 
     Cha: β-cyclohexylalanine; 
     Dhp: 3,4-dehydroproline; 
     Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid; 
     Gaba: γ-aminobutyric acid; 
     4Hppa: 3-(4-hydroxyphenyl)propionic acid; 
     Hyp:—hydroxyproline 
     3Hyp: 3-hydroxyproline; 
     4Hyp: 4-hydroxyproline; 
     hPro: homoproline; 
     4Ktp: 4-ketoproline; 
     Nle: norleucine; 
     NMe-Tyr: N-methyl-tyrosine; 
     1Nal or 1-Nal: β-(1-naphthyl)alanine; 
     2Nal or 2-Nal: β-(2-naphthyl)alanine; 
     Nva: norvaline; 
     Orn: ornithine; 
     2Pal or 2-Pal: β-(2-pyridinyl)alanine; 
     3Pal or 3-Pal: β-(3-pyridinyl)alanine; 
     4Pal or 4-Pal: β-(4-pyridinyl)alanine; 
     Pen: penicillamine; 
     (3,4,5F)Phe: 3,4,5-trifluorophenylalanine; 
     (2,3,4,5,6)Phe: 2,3,4,5,6-pentafluorophenylalanine; 
     Psu: N-propylsuccinimide; 
     Iva: Isovaline; 
     Sar: Sarcosine; 
     Taz: β-(4-thiazolyl)alanine; 
     3Thi: β-(3-thienyl)alanine; 
     Thz: thioproline; 
     Tic: tetrahydroisoquinoline-3-carboxylic acid; 
     Tle: tert-leucine; 
     Act: acetonitrile; 
     Boc: tert-butyloxycarbonyl; 
     BSA: bovine serum albumin; 
     DCM: dichloromethane; 
     DTT: dithiothrieitol; 
     ESI: electrospray ionization; 
     Fmoc: 9-fluorenylmethyloxycarbonyl; 
     HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; 
     HPLC: high performance liquid chromatography; 
     IBMX: isobutylmethylxanthine; 
     LC-MS: liquid chromatography-mass spectrometry; 
     Mtt: methyltrityl; 
     NMP: N-methylpyrrolidone; 
     5K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 5,000 Daltons. 
     10K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 10,000 Daltons. 
     20K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 20,000 Daltons. 
     30K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 30,000 Daltons. 
     40K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 40,000 Daltons. 
     50K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 50,000 Daltons. 
     60K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 60,000 Daltons. 
     PEG is available in a variety of molecular weights based on the number of repeating subunits of ethylene oxide (i.e. —OCH 2 CH 2 —) within the molecule. mPEG formulations are usually followed by a number that corresponds to their average molecular weight. For example, PEG-200 has a weight average molecular weight of 200 Daltons and may have a molecular weight range of 190-210 Daltons. Molecular weight in the context of a water-soluble polymer, such as PEG, can be expressed as either a number average molecular weight or a weight average molecular weight. Unless otherwise indicated, all references to molecular weight of mPEG herein refer to the weight average molecular weight. Both molecular weight determinations, number average and weight average, can be measured using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values can also be used, such as the use of end-group analysis or the measurement of colligative properties (e.g., freezing-point depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight or the use of light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight. 
     tBu: tert-butyl 
     TIS: triisopropylsilane 
     Trt: trityl 
     Z: benzyloxycarbonyl 
     As used herein, “PEG moiety” refers to polyethylene glycol (PEG) or a derivative thereof, for example (methoxy)polyethylene glycol (PEG m ). 
     As used herein, “PEGylated peptide” refers to a peptide wherein at least one amino acid residue, for example, Lys, or Cys has been conjugated with a PEG moiety. By “conjugated”, it is meant that the PEG moiety is either directly linked to said residue or is linked to the residue via a spacer moiety, for example a cross-linking agent. When said conjugation is at a lysine residue, that lysine residue is referred to herein as “PEGylated Lys”. A peptide that is conjugated to only one MPEG moiety is said to be “mono-PEGylated”. 
     As used herein, “Lys-PEG” and “Lys-PEG m ” refer respectively to lysine residues which have been conjugated with PEG. “Lys(epsilon-SSA-PEGn)” refers to a lysine residue wherein the epsilon-amino group has been cross-linked with MPEG using a suitably functionalized SSA. 
     In the present specification, the term “human native GIP peptide” refers to the naturally occurring human GIP peptide. This human native GIP peptide (42 amino acids) has an amino acid sequence: YAEGTFISDYSIAMDKIHQ QDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 1) and is the functionally active molecule derived from the parent precursor described in National Center for Biotechnology Information (NCBI) Reference Sequence: NP_004114.1; REFSEQ: accession NM_004123.2 This full length precursor is encoded from the mRNA sequence of human gastric inhibitory polypeptide (GIP), mRNA; ACCESSION: NM_004123; VERSION; NM_004123.2. 
     “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate polypeptide sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. 
     As used herein, “treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of a condition, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the condition or treatment, preventing emesis, i.e., by preventing the occurrence of symptoms in whole or in part associated with a condition or side-effects known to accompany a specific treatment, decreasing the rate of progression, amelioration or palliation of the symptoms associated with emesis, such as nausea and/or vomiting, and remission or improved prognosis. In some embodiments, GIP receptor agonist peptides of the disclosure are used to inhibit or delay development of emesis, i.e. nausea or vomiting or to slow the progression of emesis or the symptoms associated with emesis, or to prevent, delay or inhibit the development of emesis, nausea and/or vomiting related to the treatment of a different disease being actively treated. 
     By “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. In some embodiments, reduce or inhibit can refer to a relative reduction compared to a reference (e.g., reference level of biological activity (e.g., the number of episodes of nausea and/or vomiting after administration to a subject of a prescribed amount of chemotherapy, for example, a prescribed dose of a chemotherapeutic agent that is known to cause emesis). In some embodiments, reduce or inhibit can refer to the relative reduction of a side effect (i.e. nausea and/or vomiting) associated with a treatment for a condition or disease. 
     Optimal alignment of sequences for comparison can be conducted, for example, by the local homology algorithm of Smith and Waterman (Adv. Appl. Math. 2:482 (1981), which is incorporated by reference herein), by the homology alignment algorithm of Needleman and Wunsch (J. MoI. Biol. 48:443-53 (1970), which is incorporated by reference herein), by the search for similarity method of Pearson and Lipman (Proc. Natl. Acad. Sci. USA 85:2444-48 (1988), which is incorporated by reference herein), by computerized implementations of these algorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection. (See generally Ausubel et al. (eds.), Current Protocols in Molecular Biology, 4th ed., John Wiley and Sons, New York (1999)). 
     One illustrative example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described by Altschul et al. (J. MoI. Biol. 215:403-410 (1990), which is incorporated by reference herein). (See also Zhang et al., Nucleic Acid Res. 26:3986-90 (1998); Altschul et al., Nucleic Acid Res. 25:3389-402 (1997), which are incorporated by reference herein). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information internet web site. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al. (1990), supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Extension of the word hits in each direction is halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLAST program uses as defaults a word length (W) of 11, the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-9 (1992), which is incorporated by reference herein) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. 
     In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-77 (1993), which is incorporated by reference herein). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, an amino acid sequence is considered similar to a reference amino acid sequence if the smallest sum probability in a comparison of the test amino acid to the reference amino acid is less than about 0.1, more typically less than about 0.01, and most typically less than about 0.001. 
     Variants can also be synthetic, recombinant, or chemically modified polynucleotides or polypeptides isolated or generated using methods well known in the art. Variants can include conservative or non-conservative amino acid changes, as described below. Polynucleotide changes can result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence. Variants can also include insertions, deletions or substitutions of amino acids, including insertions and substitutions of amino acids and other molecules) that do not normally occur in the peptide sequence that is the basis of the variant, for example but not limited to insertion of ornithine which do not normally occur in human proteins. The term “conservative substitution,” when describing a polypeptide, refers to a change in the amino acid composition of the polypeptide that does not substantially alter the polypeptide&#39;s activity. For example, a conservative substitution refers to substituting an amino acid residue for a different amino acid residue that has similar chemical properties. Conservative amino acid substitutions include replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. 
     “Conservative amino acid substitutions” as referenced herein result from replacing one amino acid with another having similar structural and/or chemical properties, such as the replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. Thus, a “conservative substitution” of a particular amino acid sequence refers to substitution of those amino acids that are not critical for polypeptide activity or substitution of amino acids with other amino acids having similar properties (e.g., acidic, basic, positively or negatively charged, polar or non-polar, etc.) such that the substitution of even critical amino acids does not reduce the activity of the peptide, (i.e. the ability of the peptide to penetrate the blood brain barrier (BBB)). Conservative substitution tables providing functionally similar amino acids are well known in the art. For example, the following six groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). (See also Creighton, Proteins, W. H. Freeman and Company (1984), incorporated by reference in its entirety.) In some embodiments, individual substitutions, deletions or additions that alter, add or delete a single amino acid or a small percentage of amino acids can also be considered “conservative substitutions” if the change does not reduce the activity of the peptide. Insertions or deletions are typically in the range of about 1 to 5 amino acids. The choice of conservative amino acids may be selected based on the location of the amino acid to be substituted in the peptide, for example if the amino acid is on the exterior of the peptide and expose to solvents, or on the interior and not exposed to solvents. 
     In alternative embodiments, one can also select conservative amino acid substitutions encompassed suitable for amino acids on the interior of a protein or peptide, for example one can use suitable conservative substitutions for amino acids is on the interior of a protein or peptide (i.e., the amino acids are not exposed to a solvent), for example but not limited to, one can use the following conservative substitutions: where Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, S with A or T and A with S, G, T or V. In some embodiments, non-conservative amino acid substitutions are also encompassed within the term of variants. 
     As used herein, the term “selectivity” of a molecule for a first receptor relative to a second receptor refers to the following ratio: EC 50  of the molecule at the second receptor divided by the EC 50  of the molecule at the first receptor. For example, a molecule that has an EC 50  of 1 nM at a first receptor and an EC 50  of 100 nM at a second receptor has 100-fold selectivity for the first receptor relative to the second receptor. 
     As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se or that have a variance plus or minus of that value ranging from less than 10%, or less than 9%, or less than 8%, or less 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.1% than the stated value. For example, description referring to “about X” includes description of “X”. 
     It is understood that aspect and embodiments of the disclosure described herein include “consisting” and/or “consisting essentially” of aspects and embodiments. As used herein, the singular form “a”, “an”, and “the” includes plural references unless indicated otherwise. 
     A. GIP RECEPTOR AGONIST PEPTIDES 
     In various embodiments of the present disclosure, GIP receptor agonist peptides are provided. In addition, methods are provided for the prevention and/or treatment of diabetes mellitus (e.g., type-2 diabetes mellitus) obesity, a metabolic syndrome and emesis in a subject in need thereof. In various embodiments, the methods provide administration of a therapeutically effective amount of a GIP receptor agonist peptide once per day or QD (for example, Q1D, used interchangeably herein) to the subject. 
     As used herein, GIPr agonist peptides of the present disclosure refer to peptides that preferentially bind to GIP receptors compared to other receptors, such as GLP receptors. In some embodiments, an exemplary GIPr agonist peptide of the present disclosure are GIPr agonist peptides that have a selectivity ratio as defined as the ratio of (EC 50  GLP1R/EC 50  GIPR) greater than 10, or greater than 100, or greater than 1,000, or greater than 10,000, or greater than 100,000. An exemplary GIP receptor agonist peptide is a GIPr agonist peptide when the peptide has a selectivity ratio of (EC 50  GLP1R/EC 50  GIPR) of greater than 10, or 100, or 1,000, or 10,000, or from about 100-1,000,000 or more. 
     As used herein, “Lys(R)” is synonymous with “Km” and are used interchangeably. 
     In some embodiments, a GIP receptor agonist peptide, or a salt thereof is provided. 
     In some embodiments, the GIP receptor agonist peptide is represented by formula (I): P 1 -Tyr-A2-Glu-Gly-Thr-Phe-Ile-Ser-A9-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-A24-Trp-A26-Leu-A28-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 , or a pharmaceutically acceptable salt thereof; 
     wherein
 
P 1  represents a group represented by formula
 
     —R A1 , 
     —CO—R A1 , 
     —CO—OR A1 , 
     —CO—COR A1 , 
     —SO—R A1 , 
     —SO 2 —R A1 ,
 
—SO 2 —OR A1 ,
 
—CO—NR A2 R A3 ,
 
—SO 2 —NR A2 R A3 ,
 
—C(═NR A1 )—NR A2 R A3 , or
 
is absent,
 
wherein R A1 , R A2 , and R A3  each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
 
P 2  represents —NH 2  or —OH;
 
A2: represents Aib, D-Ala, Ala, Gly, or Pro;
 
A9: represents Asp or Leu;
 
A13: represents Aib, or Ala;
 
A14: represents Leu, Aib, Lys;
 
A16: represents Arg, Ser, or Lys;
 
A17: represents Aib, Gln, or Ile;
 
A18: represents Ala, His, or Lys;
 
A19: represents Gln, or Ala;
 
A20: represents Aib, Gln, Lys, or Ala;
 
A21: represents Asp, Asn, or Lys;
 
A24: represents Asn, or Glu;
 
A26: represents Leu or Lys;
 
A28: represents Ala, Lys, or Aib;
 
A29: represents Gln, Lys, Gly, or Aib;
 
A30: represents Arg, Gly, Ser, or Lys;
 
A31: represents Gly, Pro, or a deletion;
 
A32: represents Ser, Gly, or a deletion;
 
A33: represents Ser, Gly, or a deletion;
 
A34: represents Gly, Lys, Asn, or a deletion;
 
A35: represents Ala, Asp, Ser, Lys, or a deletion;
 
A36: represents Pro, Trp, Lys, or a deletion;
 
A37: represents Pro, Lys, Gly, or a deletion;
 
A38: represents Pro, His, Lys, or a deletion;
 
A39: represents Ser, Asn, Gly, Lys, or a deletion; and
 
A40: represents Ile, Lys or a deletion.
 
     In related embodiments, the GIP receptor agonist peptide according to Formula (I) has an amino acid sequence of Formula (I), wherein A31 is Gly and A32-A39 are deletion, or A32 is Gly and 33-A39 are deletion. 
     In various embodiments, the GIP receptor agonist peptide of Formula (I) comprises a peptide wherein P 2  is —OH. 
     On other embodiments, the GIP receptor agonist peptide of Formula (I) comprises a peptide wherein P 1  is methyl, (Me). 
     In various embodiments, the GIP receptor agonist peptide of Formula (I) comprises a peptide wherein P 1  is methyl, (Me), and P 2  is —OH. 
     In some embodiments, a GIP receptor agonist peptide, or a salt thereof is provided. The GIP receptor agonist peptide is represented by formula (II): P 1 -Tyr-A2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-A19-A20-A21-Phe-Val-A24-Trp-A26-Leu-Ala-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 , or a pharmaceutically acceptable salt thereof, wherein: 
     P 1  represents a group represented by formula 
     —R A1 , 
     —CO—R A1 , 
     —CO—OR A1 , 
     —CO—COR A1 , 
     —SO—R A1 , 
     —SO 2 —R A1 ,
 
—SO 2 —OR A1 ,
 
—CO—NR A2 R A3 ,
 
—SO 2 —NR A2 R A3 , or
 
—C(═NR A1 )—NR A2 R A3  
 
wherein R A1 , R A2 , and R A3  each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
 
P 2  represents —NH 2  or —OH;
 
A2: represents Aib, Ser, Ala, D-Ala, or Gly;
 
A13: represents Aib, Tyr, or Ala;
 
A14: represents Leu, or Lys(R);
 
A16: represents Arg, Ser, or Lys;
 
A17: represents Aib, Ile, Gln, or Lys(R);
 
A18: represents Ala, His, or Lys(R);
 
A19: represents Gln or Ala;
 
A20: represents Aib, Gln, or Lys(R);
 
A21: represents Asn, Glu, Asp, or Lys(R);
 
A24: represents Asn, or Glu;
 
A26: represents Leu or Lys(R);
 
A28: represents Ala, Aib, or Lys(R);
 
A29: represents Gln, Aib, or Lys(R);
 
A30: represents Arg, Gly, Lys, Ser, or Lys(R);
 
A31: represents Gly, Pro, or a deletion;
 
A32: represents Ser, Lys, Pro, Gly, or a deletion;
 
A33: represents Ser, Lys, Gly, or a deletion;
 
A34: represents Gly, Lys, Asn, or a deletion;
 
A35: represents Ala, Asp, Ser, Lys, or a deletion;
 
A36: represents Pro, Trp, Lys, or a deletion;
 
A37: represents Pro, Lys, Gly, or a deletion;
 
A38: represents Pro, His, Lys, or a deletion;
 
A39: represents Ser, Asn, Lys, Gly, or a deletion;
 
A40: represents Ile, Lys(R), or a deletion;
 
wherein the residue Lys(R), the (R) portion represents X-L-, wherein L represents a linker, and is selected from the following group consisting of gE, GGGGG, GGEEE, G2E3, G3gEgE, 2OEGgEgE, OEGgEgE, GGPAPAP, 2OEGgE, 3OEGgEgE, G4gE, G5gE, 2OEGgEgEgE, 2OEG and G5gEgE; and X represents a lipid.
 
     In some embodiments, a GIP receptor agonist peptide, or a salt thereof is provided. The GIP receptor agonist peptide is represented by formula (III): P 1 -Tyr-A2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-A24-Trp-A26-Leu-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 , or a pharmaceutically acceptable salt thereof, wherein: 
     P 1  represents a group represented by formula 
     —R A1 , 
     —CO—R A1 , 
     —CO—OR A1 , 
     —CO—COR A1 , 
     —SO—R A1 , 
     —SO 2 —R A1 ,
 
—SO 2 —OR A1 ,
 
—CO—NR A2 R A3 ,
 
—SO 2 —NR A2 R A3 , or
 
—C(═NR A1 )—NR A2 R A3  
 
wherein R A1 , R A2 , and R A3  each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
 
P 2  represents —NH 2  or —OH;
 
A2: represents Aib, D-Ala, Ala, Ser, or Gly;
 
A13: represents Aib, Tyr, or Ala;
 
A14: represents Leu, or Lys(R);
 
A16: represents Arg, Ser, or Lys;
 
A17: represents Aib, Ile, Gln, or Lys(R);
 
A18: represents Ala, His, or Lys(R);
 
A20: represents Aib, Gln, or Lys(R);
 
A21: represents Asp, Asn, Glu, or Lys(R);
 
A24: represents Asn, or Glu;
 
A26: represents Leu, or Lys(R);
 
A28: represents Ala, Aib, or Lys(R);
 
A29: represents Gln, Aib, Gly, or Lys(R);
 
A30: represents Arg, Lys, Ser, or Lys(R);
 
A31: represents Gly, Pro, or a deletion;
 
A32: represents Ser, Gly, or a deletion;
 
A33: represents Ser, Gly, or a deletion;
 
A34: represents Gly, Lys, or a deletion;
 
A35: represents Ala, Lys, Ser, or a deletion;
 
A36: represents Pro, Lys, or a deletion;
 
A37: represents Pro, Lys, Gly, or a deletion;
 
A38: represents Pro, Lys, or a deletion;
 
A39: represents Ser, Lys, Gly, or a deletion;
 
A40: represents Lys(R) or a deletion; and
 
wherein the residue Lys(R), the (R) portion represents X-L-, wherein L represents a linker, and is selected from the following group consisting of 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG and G5gEgE; and X represents a lipid.
 
     In some embodiments, a GIP receptor agonist peptide, or a salt thereof is provided. The GIP receptor agonist peptide is represented by formula (IV): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-Asn-Trp-Leu-Leu-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P 2 , or a pharmaceutically acceptable salt thereof; 
     wherein
 
P 1  represents H, C 1-6  alkyl, or absent;
 
P 2  represents —NH 2  or —OH;
 
A2 represents Aib, Gly, or Ser;
 
A6 represents Phe or Leu;
 
A7 represents Ile or Thr;
 
A13 represents Ala, Aib, or Tyr;
 
A14 represents Leu, Lys, or Lys(R);
 
A16 represents Lys, Arg, or Ser;
 
A17 represents Aib, Ile, Lys, or Lys(R);
 
A18 represents Ala, His, Lys, or Lys(R);
 
A20 represents Gln, Lys, Lys(R), or Aib;
 
A21 represents Asp, Lys, Lys(R), or Asn;
 
A28 represents Ala, Aib, or, Lys, Lys(R);
 
A29 represents Gln, Lys, Lys(R), or Aib;
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac);
 
A31 represents Pro, Gly, or a deletion;
 
A32 represents Ser, Gly, or a deletion;
 
A33 represents Ser, Gly, or a deletion;
 
A34 represents Gly, Lys, or a deletion;
 
A35 represents Ala, Ser, Lys, or a deletion;
 
A36 represents Pro, Lys, or a deletion;
 
A37 represents Pro, Lys, Gly, or a deletion;
 
A38 represents Pro, Lys, or a deletion; and
 
A39 represents Ser, Gly, Lys, or a deletion,
 
wherein in the residue Lys(R), the (R) portion represents X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE; and X represents C 14 -C 18  monoacid or C 14 -C 18  diacid.
 
     In some embodiments, A2 represents Aib. 
     In some embodiments, A6 represents Phe. 
     In some embodiments, A7 represents Ile. 
     In some embodiments, A13 represents Ala or Aib. 
     In some embodiments, A16 represents Arg. 
     In some embodiments, A31 represents Pro or Gly, and A32-A39 is deletion. 
     In some embodiments of formula (IV), A14 represents Leu or Lys(R). 
     In some embodiments of formula (IV), A17 represents Aib, Ile, or Lys(R). 
     In some embodiments of formula (IV), A17 represents Aib or Lys(R). 
     In some embodiments of formula (IV), A18 represents Ala, His, or Lys(R). 
     In some embodiments of formula (IV), A20 represents Gln, Lys(R), or Aib. 
     In some embodiments of formula (IV), A21 represents Asp, Lys(R), or Asn. 
     In some embodiments of formula (IV), A28 represents Ala, Aib, or Lys(R). 
     In some embodiments of formula (IV), A29 represents Gln, Lys(R), or Aib. 
     In some embodiments of formula (IV), A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac). 
     In some embodiments of formula (IV), A30 represents Ser, Arg, Lys(R), or Lys(Ac). 
     In some embodiments of formula (IV), 
     A14 represents Leu or Lys(R);
 
A17 represents Aib, Ile, or Lys(R);
 
A18 represents Ala, His, or Lys(R);
 
A20 represents Gln, Lys(R), or Aib;
 
A21 represents Asp, Lys(R), or Asn;
 
A28 represents Ala, Aib, or Lys(R);
 
A29 represents Gln, Lys(R), or Aib; and
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac).
 
     In some embodiments of formula (IV), 
     A2 represents Aib;
 
A17 represents Aib, Lys, or Lys(R);
 
A20 represents Aib; and
 
A28 represents Ala or Aib,
 
wherein L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3, G4gE, G4gEgE, G5, G5E, G5gE, G5gEgE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE.
 
     In some embodiments of formula (IV), 
     A2 represents Aib;
 
A14 represents Leu or Lys(R);
 
A17 represents Aib or Lys(R);
 
A18 represents Ala, His, or Lys(R);
 
A20 represents Aib;
 
A21 represents Asp, Lys(R), or Asn;
 
A28 represents Ala or Aib;
 
A29 represents Gln, Lys(R), or Aib; and
 
A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac),
 
wherein L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3, G4gE, G4gEgE, G5, G5E, G5gE, G5gEgE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE.
 
     In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein P 2  is —OH. In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein P 2  is —NH 2 . 
     In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein P 1  is a C 1-6  alkyl group. In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein P 1  is methyl, (Me). 
     In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein P 1  is Me and P 2  is —OH. 
     In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein L is 2OEGgEgE or GGGGG. 
     In some embodiments, the GIP receptor agonist peptide comprises a peptide wherein X is C 15  diacid or C 16  diacid. 
     In some embodiments, the GIPR agonist peptide or the pharmaceutically acceptable salt thereof is represented by Formula (V): P 1 -Tyr-Aib-Glu-Gly-The-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-Leu-Asp-Arg-Aib-A18-Gln-Aib-A21-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-A30-A31-A32-P 2 , wherein 
     P 1  is methyl;
 
P 2  is OH or NH 2 ;
 
A13 represents Ala or Aib;
 
A18 represents Ala, Lys, or Lys(R);
 
A21 represents Lys, Lys(R), or Asp;
 
A30 represents Lys or Ser;
 
A31 represents Gly or Pro; and
 
A32 represents Gly or deletion;
 
wherein (R) represents X-L-, L represents 2OEGgEgE or GGGGG; and X represents a C 15  diacid or C 16  diacid.
 
     In some embodiments of formula (V), A18 represents Ala or Lys(R). 
     In some embodiments of formula (V), A21 represents Lys(R) or Asp. 
     In some embodiments of Formula (V), the GIPR agonist peptide or the pharmaceutically acceptable salt thereof is represented by the following formula: P 1 -Tyr-Aib-Glu-Gly-The-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-A13-Leu-Asp-Arg-Aib-A18-Gln-Aib-A21-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-A30-A31-A32-P 2 , wherein 
     P 1  is methyl;
 
P 2  is OH or NH 2 ;
 
A13 represents Ala or Aib;
 
A18 represents Ala or Lys(R);
 
A21 represents Lys(R) or Asp;
 
A30 represents Lys or Ser;
 
A31 represents Gly or Pro; and
 
A32 represents Gly or deletion;
 
wherein (R) represents X-L-, L represents 2OEGgEgE or GGGGG; and X represents a C 15  diacid or C 16  diacid.
 
     In various embodiments, an illustrative GIP receptor agonist peptide for use in the methods, compositions and medicaments exemplified herein, has at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity to any GIP receptor agonist peptide as defined by formulas (I), (II), (III), (IV), or (V). 
     In various embodiments, an illustrative GIP receptor agonist peptide for use in the methods, compositions and medicaments exemplified herein, has 100% sequence identity to any GIP receptor agonist peptide as defined by formulas (I), (II), (III), (IV), or (V). 
     In various embodiments, the GIP receptor agonist peptide as defined by formulas (I), (II), (III), (IV), or (V), has a P 2  defined by a hydroxyl (—OH) group. In various embodiments, the GIP receptor agonist peptide as defined by formulas (I), (II), (III), (IV), or (V), has a P 2  defined by an amino (—NH 2 ) group. 
     In various embodiments, the GIP receptor agonist peptide as defined by formulas (I), (II), (III), (IV), or (V), has a P 1  defined by a C 1-6  alkyl group. In some embodiments, P 1  is a methyl (Me) group. 
     With reference to the above GIP receptor agonist peptides as defined by formulas (I), (II), (III), (IV), and (V), in various embodiments, a GIP receptor agonist peptide has at least one amino acid having a bivalent substituent, covalently coupled to a side chain of an amino acid. For example, in some embodiments, a GIP receptor agonist peptide has an amino acid sequence having a side chain of at least one amino acid, or modified amino acid for example, a Lys residue of the GIP receptor agonist peptide being covalently attached to a substituent group (R). In various embodiments, a Lys residue of the GIP receptor agonist peptide may be covalently attached to a substituent (R) as shown in the present disclosure as Lys(R). 
     For example, a selective GIP receptor agonist peptide of the present disclosure may have a Lys residue substituted by an (R) group at an amino acid position A14-A30, for example, at amino acid position: A14, or A17, A18, A20, A21, A28, A29, or A30. In various embodiments, the (R) group represents X-L-, wherein L represents a bivalent linker. In some embodiments, the bivalent linker can include a PEG, Abu-, (Gly)(2-8)-, gGlu(1-3)-, gE, GGGGG, GGEEE, G2E3, G3gEgE, 2OEGgEgE, OEGgEgE, GGPAPAP, 2OEGgE, 3OEGgEgE, G4gE, G5gE, 2OEGgEgEgE, 2OEG and G5gEgE one to ten amino acids, for example, a glycine linker having two to ten glycine residues, two to six or from five to six glycines linked, or combinations of the foregoing linkers. In these embodiments, X represents a substituent group, for example, a lipid. In various embodiments, X represents a monoacid or diacid lipid having C 14  to C 16  carbons in length, for example, a C 14 , a C 15 , a C 16  monoacid or diacid lipid. In various embodiments, X represents a monoacid or diacid lipid having C 14  to C 18  carbons in length, for example, a C 15 , a C 16 , a C 18  monoacid or diacid lipid. In some embodiments, X is a C 15  diacid, C 16  diacid, or C 18  diacid. In some embodiments, X is a C 15  diacid or C 16  diacid. In some embodiments, X is a C 18  diacid. 
     In various embodiments, the GIP receptor agonist peptide may include one or two Lys residues is substituted with an X-L- substituent. In some embodiments, a Lys residue is substituted with an X-L- substituent, wherein L represents (PEG3)2-, Abu-, (Gly)(2-8)-, gGlu(1-3)-, or combinations thereof, for example, (PEG3)2-gGlu-, Abu-gGlu-, (Gly)s-gGlu-, or (Gly) 6 -gGlu-, GGGGG-, (PEG3)2-, PEG3)2-(Gly)5-6-, gE, GGGGG, GGEEE, G2E3, G3gEgE, 2OEGgEgE, OEGgEgE, GGPAPAP, 2OEGgE, 3OEGgEgE, G4gE, G5gE, 2OEGgEgEgE, 2OEG and G5gEgE, or combinations thereof. 
     In some embodiments, the GIP receptor agonist peptide has one, or two Lys residues having a substituted side chain. For example, a selective GIPr agonist peptide may have a Lys residue substituted by X-L-, wherein L represents a bivalent linker, as discussed herein, for example, L may represent a bond or a bivalent substituent group, and wherein X represents an optionally substituted hydrocarbon group, for example a monoacid or diacid lipid, or a salt thereof. In some embodiments, the bivalent substituent group comprises: an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof. 
     In various embodiments, the GIP receptor agonist peptide may include one, or two Lys residues which may be substituted with an (R) group defined as an X-L- substituent. In some embodiments, Lys(R) is a Lys residue having a side chain substituted with X-L-. In related embodiments, the GIP receptor agonist peptide, the X moiety can be an optionally substituted hydrocarbon. In some embodiments, the X moiety in the X-L- substituent can include a C 17 -C 22  monoacid, a C 17 -C 22  diacid, an acetyl group, or combinations thereof Some exemplary X moieties may include: (Teda:C14 diacid), (Peda:C15 diacid), (Heda:C16 diacid). 
     In various embodiments, a GIP receptor agonist peptide of formulas (I) to (V), the L moiety of the X-L- group can include, a bivalent linker. In some examples, the bivalent linker can include PEG, Abu-, (Gly) (2-8) -, gGlu (1-3) -, one to ten amino acids, or combinations thereof. In these examples of X-L, X may represents a substituent group. 
     In some embodiments, (R) represents X-L- wherein L represents (PEG3)2-, Abu-, (Gly) (2-8) -, gGlu (1-3) -, or combinations thereof. In some embodiments, L represents (PEG3)2-gGlu-, Abu-gGlu-, (Gly) 5 -gGlu, (Gly) 6 -gGlu-, GGGGG-, GGGGGG-, (PEG3)2-, or (PEG3)2-(Gly) 5-6 -, GGGGG-, (PEG3)2-, PEG3)2-(Gly)5-6-, gE, GGGGG, GGEEE, G2E3, G3gEgE, 2OEGgEgE, OEGgEgE, GGPAPAP, 2OEGgE, 3OEGgEgE, G4gE, G5gE, 2OEGgEgEgE, 2OEG and G5gEgE, or combinations thereof. 
     In some related embodiments, L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof For example, an illustrative GIP receptor agonist peptide has a Lys(R) residue, wherein the (R) portion of the Lys(R) residue is represented as X-L-, wherein X is a bivalent substituent group comprising an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof. 
     In some embodiments, an illustrative Lys(R) can include an (R) group defined as X-L- group, wherein the bivalent substituent X is a C 14 -C 16  monoacid, a C 14 -C 18  diacid, a C 17 -C 22  diacid or an acetyl group. Some exemplary X moieties may include: (Teda:C14 diacid), (Peda:C15 diacid), (Heda:C16 diacid). 
     In some embodiments, an illustrative GIP receptor agonist peptide of formulas (I), (II), (III), (IV), or (V), can include a peptide having one, to two Lys(R) lipidated amino acids positioned in the amino acid sequence of the peptide ranging from residue A14 to A30, wherein the Lys(R) residue has a substituted side chain defined by X-L-. In exemplary embodiments, the X-L- group of the Lys(R) residue in the illustrative GIP receptor agonist peptide of formulas (I), (II), (III), (IV), or (V), may include: -(g-Glu) 2 -Oda, -(g-Glu) 2 -Eda, -(g-Glu) 2 -Heda, -(PEG3)2-gGlu-Eda, -(PEG3)2-gGlu-Heda, -(PEG3)2-gGlu-Oda, -(PEG3)2-gGlu-Ida, -(PEG3)-gGlu-Eda, -(PEG3)-gGlu-Heda, -(PEG3)-gGlu-Oda, -Abu-gGlu-Oda, -(Gly) 5 -gGlu-Eda, -(Gly) 5 -gGlu-Heda, -(Gly) 5 -gGlu-Oda, -(Gly) 5 -Heda, -(Gly) 5 -Oda, -(Gly) 5 -Eda, -(PEG3)2-Heda, -(PEG3)2-Eda, -(PEG3)2-Oda, 2OEGgEgE-Teda:C14 diacid, OEGgEgE-Teda:C14 diacid, 2OEGgE-Teda:C14 diacid, 3OEGgEgE-Teda:C14 diacid, G5gEgE-Teda:C14 diacid, 2OEGgEgEgE-Teda:C14 diacid, 2OEG-Teda:C14 diacid, G5gEgE-Teda:C14 diacid, 2OEGgEgE-Peda:C15 diacid, OEGgEgE-Peda:C15 diacid, 2OEGgE-Peda:C15 diacid, 3OEGgEgE-Peda:C15 diacid, G5gEgE-Peda:C15 diacid, 2OEGgEgEgE-Peda:C15 diacid, 2OEG-Peda:C15 diacid, G5gEgE-Peda:C15 diacid, 2OEGgEgE-Heda:C16 diacid, OEGgEgE-Heda:C16 diacid, 2OEGgE-Heda:C16 diacid, 3OEGgEgE-Heda:C16 diacid, G5gEgE-Heda:C16 diacid, 2OEGgEgEgE-Heda:C16 diacid, 2OEG-Heda:C16 diacid, G5gEgE-Heda:C16 diacid, or combinations thereof. 
     In some illustrative examples, the (R) group may be covalently linked to a side chain of a Lys amino acid. In some examples, an exemplary (R) group represents X-L-, wherein L represents a bivalent linker comprising PEG and/or two or more amino acids, and X represents a substituent group, or a salt thereof. In various embodiments, the GIP receptor agonist peptide of formulas (I)-(V) or a salt thereof, has one or two Lys(R), residues located at a position between A14 to A30, wherein (R) represents a substituent group. 
     In some embodiments, R represents X-L-, wherein L is one or a combination of more than one selected from 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, G5gEgE, and X represents C 14 -C 16  monoacid or diacid lipid, or an acetyl group. 
     Alternatively, in some embodiments, (R) represents X-L-, wherein L represents a linker selected from 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, and G5gEgE, and X represents C 14 -C 16  linear saturated dicarboxylic acid. 
     In various embodiments, in each of the examples of GIP receptor agonist peptides of formulas (I) to (V), at least one amino acid between A14 to A30, or from A14 to A21, or A14 or A21 is Lys(R), wherein (R) represents X-L-, wherein L represents a bivalent linker L, wherein L represents 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, or G5gEgE. In some related embodiments, (R) represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof. In various embodiments related to the various L moiety exemplifications, (R) represents X-L, wherein L is discussed above and X is a C 14 -C 16  monoacid, or a C 14 -C 16  diacid or an acetyl group. For example, in some embodiments, X is (Teda:C14 diacid), (Peda:C15 diacid), (Heda:C16 diacid). In various embodiments, an exemplary GIP receptor agonist peptide of formulas (I) to (V), comprises a peptide having at least one Lys amino acid positioned between A14 to A30, or from A14 to A21, for example, at an amino acid position A14, or A17, A18, A20, A21, A26, A29, or A30 of the peptide. The (R) substituent portion of the Lys(R) residue, represents X-L-, wherein L represents a bivalent linker L, for example, L represents 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, or G5gEgE and X is a C 14 -C 16  monoacid, or a C 14 -C 16  diacid or an acetyl group, for example, a C 14  monoacid or a C 14  diacid or a C 15  monoacid or a C 15  diacid or a C 16  monoacid or a C 16  diacid. In various embodiments, an exemplary GIP receptor agonist peptide of formulas (I) to (V), comprises at least one Lys amino acid positioned between A14 to A30, or from A14 to A21, or A14 or A21, wherein (R) represents X-L-, wherein L represents a bivalent linker L, wherein L represents 2×γGlu-2×OEG (miniPEG), and X is a C 15  monoacid or C 15  diacid. 
     In some embodiments, (R) represents X-L-, wherein L represents a bivalent linker comprising PEG and/or amino acid or consisting of PEG and/or one or more amino acids, for example, a Gly 2-10 -linker, and X represents a substituent group. A known PEG linker, an amino acid linker or combinations thereof may be used as illustrative examples of a bivalent linker, as long as it is able to link Lys to a substituent group. Alternatively, in some embodiments, R represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof A known bivalent substituent group may include, but is not limited to, an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof may be used. 
     In some embodiments, L represents (PEG3)2-, Abu-, (Gly) (2-10) -, gGlu (1-3) -, or combinations thereof. In some embodiments, L represents (PEG3)2-gGlu-. In some examples, L represents Abu-gGlu-. In other examples, L represents (Gly) 5 -gGlu-, or (Gly) 6 -gGlu-. In some embodiments, L represents a glycine peptide having from about two to about ten glycines linked, or from about two to about seven glycines linked. In some examples, L represents (Gly) 5-6 -, or (Gly) 5 -, GGGGG-, or GGGGG-gGlu-. In some examples, L represents 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, or G5gEgE. 
     In some embodiments, L represents (PEG3)2-. In some embodiments, L represents (Gly) 2-10 -, for example, (Gly) (5-6) . In some further embodiments, L represents a combination of groups, such as one or more PEG molecules linked to a glycine peptide: Gly 2-10  for example, L may be (PEG3)2-(Gly) 5-6 -, or (PEG3)2-(Gly) 5 -. 
     In some embodiments, the (R) group attached to an amino acid, for example, a Lys residue represents X-L-, wherein L represents a bivalent linker comprising PEG and/or one or more amino acids or consisting of PEG and/or one or more amino acids, and X represents a substituent group. A known PEG linker, an amino acid linker or combinations thereof may be used as the bivalent linker as long as it is able to link, a Lys residue to a substituent group. Alternatively, R represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof. A known bivalent substituent group including, but are not limited to, an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof may be used. In some embodiments, (R) represents X-L-, wherein L is one or a combination of more than one selected from: 
     
       
         
         
             
             
         
       
     
     a glycine linker comprising one or two to nine-linked glycine(s) or a single bond, and X represents C 17 -C 22  monoacid or diacid, or an acetyl group. In some embodiments, a linker L, can be coupled or linked covalently to a side chain of at least one amino acid, or modified amino acid for example, a Lys residue of the GIP receptor agonist peptide being covalently attached to a substituent group. In an embodiment, the selective GIP receptor agonist peptide is covalently attached to an (R) group, wherein the (R) group is a hydrophilic polymer, and the Lys(R) residue is positioned at an amino acid position ranging from A14 to A30. In an embodiment, the selective GIP receptor agonist peptide is covalently attached to a hydrophilic polymer, for example, the hydrophilic polymer is a polyethylene glycol (PEG) molecule or a variant thereof. 
     In some embodiments, the linker L is a PEG molecule, for example, PEG3(n), PEG(2)(n), or mPEG having a weight average molecular weight of about 5-30 kDa. In some embodiments, L can be any combination of PEG3(n), PEG(2)(n), gGlu(n), D-gGlu(n), AMBZ(n), GABA(n), G(x), NpipAc(n), Tra(n), eLya(n), where n=1-5 and x=1-10. Exemplary PEG linkers can be used as part of an (R) group in a substituted Lys residue, for example, located at one or more of A14-A30, for example, at an amino acid position: A14, A17, A18, A20, A21, AA26, A29, or A30, wherein the MPEG linker can include one or more of the following additional MPEG linkers: 
     
       
         
         
             
             
         
       
     
     In some embodiments, exemplary MPEG linkers which may be used for coupling a substituent X to a Cys amino acid can include a MPEG molecule having an weight average molecular weight of about 5-30 kDa. In some embodiments, illustrative PEG linkers for attachment to a Cys side chain can include: 
     
       
         
         
             
             
         
       
     
     In various examples, R represents X-L-, wherein X-L- represents Teda-GGGG-(Teda:C14 diacid), Teda-GGGGG-, Teda-GGGGGG-, Peda-GGGG-(Peda:C15 diacid), Peda-GGGGG-, Peda-GGGGGG-, Heda-GGGG-(Heda:C16 diacid), Heda-GGGGG-, Heda-GGGGGG-, Heda-GGGGGGGGG-. 
     Alternatively, the (R) group represents X-L-, wherein L represents a glycine linker comprising five or six-linked glycines, and X represents C 14 -C 16  linear saturated dicarboxylic acid. 
     Alternatively, the (R) group represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an a C 14 -C 16  fatty acid, or a C 14 -C 16  acylated fatty acid or a C 14 -C 16  dicarboxylic acid, or a salt thereof. In some embodiments, the X represents a palmitic fatty acid used to add a palmitoyl group to the epsilon amine side group of a Lys residue, for example, a Lys reside in the GIP receptor agonist peptide. 
     In other embodiments, the GIP receptor agonist peptide has one, or two modified lysine residues, i.e. Lys(R), wherein the (R) group represents X-L-, wherein L represents a glycine linker comprising three, four, five or six-linked glycines, and X represents C 14 -C 16  linear saturated dicarboxylic acid. In an embodiment, the acyl group is a C 14  to C 16  fatty acyl group, for example a palmitoyl or myristoyl fatty acyl group. 
     In an embodiment, the GIP receptor agonist peptide is covalently attached to an (R) group, wherein the (R) group is a hydrophilic polymer at any amino acid position ranging from A14 to A30. In an embodiment, the GIP receptor agonist peptide is covalently attached to a hydrophilic polymer at amino acid position, A14, A17, A18, A20, A21, A26, A29, or A30, or combinations thereof, for example, at positions A14-A30 or from A14 to A21. For example, the hydrophilic polymer may be attached to the side chain of a Lys residue of the GIP receptor agonist peptide. In an embodiment, the hydrophilic polymer is a polyethylene glycol (mPEG). The mPEG polymer may also be further conjugated to a glycine linker, i.e. (Gly) (2-8) -, or to one or more gGlu- residues, for example, gGlu (1-3) -. In some examples, the mPEG has a weight average molecular weight of about 1,000 Daltons to about 60,000 Daltons, such as about 5,000 Daltons to about 40,000 Daltons, or about 1,000 Daltons, or 5,000 Daltons, or 10,000 Daltons, or 12,000 Daltons, or 14,000 Daltons to about 20,000 Daltons. 
     In some embodiments, methods for conjugating a polyethylene glycol (mPEG) polymer to a reactive amine or sulfhydryl group is well known in the art. For example, mPEG can be conjugated to a lysine amine sidechain using an amine-reactive pegylated crosslinker. A Bis(succinimidyl)penta-(ethylene glycol) spacer arm can be used as a homobifunctional, amine-to-amine crosslinker that contain N-hydroxy-succinimide (NHS) esters at both ends of a mPEG spacer arm. An amine-reactive crosslinker that contains a PEG spacer arm. A bis-succinimide ester-activated mPEG compound may be used for crosslinking between primary amines (—NH 2 ) in GIP receptor agonist peptides of the present disclosure. The N-hydroxysuccinimide ester (NHS) groups at either end of the mPEG spacer react specifically and efficiently with lysine and N-terminal amino groups at pH 7-9 to form stable amide bonds. Other homobifunctional, sulfhydryl-reactive crosslinkers that contain the maleimide group at either end of a PEG spacer may be used to couple PEG to a Cys amino acid of a GIP receptor agonist peptide. Heterofunctional crosslinking spacer arms may also be used when two different reactive groups are used as the linkage groups, e.g. an amine group and a sulfhydryl group. A sulfhydryl-reactive crosslinker that contains a PEG spacer arm, may be used to couple a PEG polymer to a GIP receptor agonist peptide. In some embodiments, a bismaleimide-activated PEG compound may be used for crosslinking between sulfhydryl (—SH) groups in proteins and other thiol molecules. The maleimide groups at either end of the PEG spacer may react specifically and efficiently with reduced sulfhydryls at pH 6.5-7.5 to form stable thioether bonds. In other embodiments, direct coupling of a PEG molecule to a GIP receptor agonist peptide may be accomplished using known methods in the art. For example, a well known technique whereby a peptide may be covalently modified with PEG groups requiring PEG compounds that contain a reactive or targetable functional group at one end. The simplest method to pegylate peptides, which are rich in surface primary amines, is to use a PEG compound that contains an NHS ester group at one end, for example, a methyl-(PEG)n-NHS ester. In a similar fashion, methyl-(PEG)n-maleimide (wherein n can be from 20-300) may be used to couple a PEG molecule to a Cys containing peptide of the present disclosure. Methods known in the art for conjugation of polyethylene glycol polymers of various lengths ranging from 1,000 Daltons to 20,000 Daltons or more are provided in 1. Hermanson, G. T. (2013). 3rd Edition. Bioconjugate Techniques, Academic Press, Veronese, F. and Harris, J. M. Eds. (2002). Peptide and protein PEGylation. Advanced Drug Delivery Review 54(4), 453-609, Zalipsky, S., et al., “Use of Functionalized Poly(Ethylene Glycols) for Modification of Polypeptides” in Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, Plenus Press, New York (1992), and in Zalipsky (1995) Advanced Drug Reviews 16:157-182 the disclosures of all of these references are hereby incorporated by reference herein in their entireties. 
     In various embodiments, the GIP receptor agonist peptide disclosed herein with the lipidated Lys(R) residues positioned between amino acids A14 and A30, for example, at amino acid positions A14, A17, A18, A20, A21, A28, A29, or A30, provide GIPR agonist peptides having enhanced ½ life of elimination, % remaining after 48 hours in serum, and solubility in various media, when compared to GIPR agonist peptides in the art. In some embodiments, the position of the lipidated lysine residue, the sequence of the GIPR peptide and the length of the lipid used in the (R) substituent on the Lys residue play a role in the improved half life and solubility of the GIPR peptide, that enables the GIPR agonist peptides to be dosed in a therapeutically effective way to a subject in need of antiemetic activity once per day (Q1D), for example, once per 24 hours. The enhanced 12 life of elimination, % remaining after 48 hours in serum, and solubility in various media are illustrated in the Examples section of the present disclosure. 
     In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D, or once per day dosing to treat emesis, including nausea and/or vomiting, have a human intravenous T½ life of elimination in human serum, ranging between 4-10 hours, or for example, ranging between 4-6 hours. In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing to treat emesis, including nausea and/or vomiting, have a solubility of greater than 10 mg/mL, or greater than 15 mg/mL, or greater than 20 mg/mL, or greater than 30 mg/mL, or greater than 40 mg/mL, or greater than 50 mg/mL, or greater than 60 mg/mL, or greater than 75 mg/mL, or greater than 100 mg/mL, or greater than 125 mg/mL (for example, when tested in a dissolution test using phosphate buffer at pH 7.4 performed at 37° C.); and a human intravenous T½ life of elimination in human serum ranging between 5 to 20 hours, or for example, ranging between 8 to 16 hours, or from 10 to 15 hours. In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing to treat emesis, including nausea and/or vomiting, in a mammal, for example, a human, have a solubility of 15 mg/mL, or greater; and a human intravenous T½ life of elimination ranging between 8-16 hours, or for example, ranging between 10-15 hours. In various embodiments, the GIPR agonist peptides of the present disclosure have a T½ life of elimination in humans ranging from 10 to 16 hours as determined with the methods of the Examples below, and a solubility greater than 25 mg/mL, for example, greater than 30 mg/mL, or greater than 40 mg/mL, or greater than 45 mg/ml, or greater than 50 mg/mL or higher. 
     In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing to treat emesis, including nausea and/or vomiting, in a mammal, for example, a human, have a solubility of 15-100 mg/mL, or greater; and a human intravenous T½ life of elimination ranging from 10 to 16 hours as determined with the methods of the Examples below, and a an amino acid sequence length of 30-31 or 39 amino acids, a substituted (Lys(R) Lysine residue positioned in the amino acid position of 14 or 21, a lipid characterized as a C15 diacid and a linker selected from 2OEGgEgE or GGGGG. 
     Solubility of the GIPR peptides may be determined by dissolution in a phosphate buffer followed by quantitation using liquid chromatography, for example, High Performance Liquid Chromatography (HPLC). An illustrative method is provided. For determination of the solubility of the GIPr agonist peptides, 3 mg of peptides are weighted out in a small glass vial. 100 μL of 200 mM Phosphate buffer pH 7.4 are added and the vial is sonicated/vortexed as necessary for a maximum of 1 min. A visual inspection is performed, If the sample is fully dissolved, the solubility is recorded as 30 mg/mL. If insoluble material is observed in the tube the addition of 100 μL of buffer and mixing is repeated until complete dissolution. If the peptide is not soluble in 500 μL of buffer, it is labeled as solubility &lt;6 mg/mL. The solubility can be confirmed by RP-HPLC after filtration on 0.2 μm filter on an Agilent 1200 system with a Kinetex column form Phenomenex® (2.6 μm EVO C18 100 Å, LC Column 50×3.0 mm) kept at 40° C., the eluent A is 0.05% TFA in Water, B is 0.035% TFA in Acetonitrile at a 0.6 ml/min flow rate. The gradient was from 20 to 70 over 5 min, the column is then washed for 1 min at 90% B. UV monitoring at 215 nm was used to monitor peptide concentration. Standards, may also be run on the same chromatographical experiment, to obtain standard measurements at 215 nm, from which a standard curve may be calculated and soluble peptide concentrations may be extrapolated from the standard curve. 
     In various embodiments, the GIP receptor agonist peptide disclosed herein, for example, as used in the preparation of a medicament, a composition, or for use in the prevention and/or treatment of a condition, or disorder, or in a method of prevention and/or treatment as disclosed herein, as represented by a GIP receptor agonist peptide has an amino acid sequence as provided in any one of formulas (I)-(V). 
     In various embodiments, suitable GIPR agonist peptides having the appropriate pharmacokinetics and pharmacodynamics required for therapeutically effective treatment of a subject with emesis or displaying one or more symptoms of emesis, or for use to prevent emesis by dosing Q1D, or once per day, for example, once per 24 hours have the following amino acid sequence and lipid-linker characteristics: 
     
       
         
           
               
             
               
                 TABLE 1  
               
             
            
               
                   
               
               
                 Exemplary GIPR Agonist Peptides of the 
               
               
                 Present Disclosure. 
               
            
           
           
               
               
               
               
            
               
                 Compound 
                 Amino Acid Sequence  
                   
                   
               
               
                 No. 
                 (One Letter Residue) 
                 Linker 
                 Lipid 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 14 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R- 
                 2OEGgEgE 
                 C15 
               
               
                   
                 Aib-A-Q-Aib-Km-F-V-N-W-L-L-A-Q-R-NH 2   
                   
                 diacid 
               
               
                   
               
               
                 17 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R- 
                 2OEGgEgE 
                 C15 
               
               
                   
                 Aib-Km-Q-Aib-N-F-V-N-W-L-L-A-Q-S-P-S- 
                   
                 diacid 
               
               
                   
                 S-G-A-P-P-P-S-NH 2   
                   
                   
               
               
                   
               
               
                 25 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-L-D-R- 
                 2OEGgEgE 
                 C15 
               
               
                   
                 Aib-A-Q-Aib-Km-F-V-N-W-L-L-A-Q-K-G-OH 
                   
                 diacid 
               
               
                   
               
               
                 142 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-Km-D- 
                 GGGGG 
                 C15 
               
               
                   
                 R-Aib-A-Q-Aib-D-F-V-N-W-L-L-A-Q-R-G-OH 
                   
                 diacid 
               
               
                   
               
               
                 21 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-L-D- 
                 2OEGgEgE 
                 C15 
               
               
                   
                 R-Aib-A-Q-Aib-N-F-V-N-W-L-L-A-Q-Km-P- 
                   
                 diacid 
               
               
                   
                 S-S-G-A-P-P-P-S-NH 2   
                   
                   
               
               
                   
               
               
                 48 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-A-Km-D- 
                 GGGGG 
                 C15 
               
               
                   
                 R-Aib-A-Q-Aib-N-F-V-N-W-L-L-A-Q-S-P- 
                   
                 diacid 
               
               
                   
                 S-S-G-A-P-P-P-S-OH 
                   
                   
               
               
                   
               
               
                 20 
                 Me-Y-Aib-E-G-T-F-I-S-D-Y-S-I-Aib-L- 
                 2OEGgEgE 
                 C15 
               
               
                   
                 D-R-Km-A-Q-Aib-N-F-V-N-W-L-L-A-Q-R- 
                   
                 diacid 
               
               
                   
                 P-S-S-G-A-P-P-P-S-NH 2   
               
               
                   
               
            
           
         
       
     
     In various embodiments, exemplary GIP receptor agonist peptides having a structure as defined in any one of formulas (I)-(V), are provided in  FIGS. 1A-1H . 
     B. SYNTHESIS GIPR AGONIST PEPTIDES 
     The GIP receptor agonist peptide may be synthesized according to a peptide synthesis method known in the art. The peptide synthesis method may be any of, for example, a solid phase synthesis process and a liquid phase synthesis process. That is, the object GIP receptor agonist peptide can be produced by repeating condensation of a partial peptide or amino acid capable of constituting the GIP receptor agonist peptide, and the remaining portion (which may be constituted by two or more amino acids) according to a desired sequence. When a product having the desirable sequence has a protecting group, the object GIP receptor agonist peptide can be produced by eliminating a protecting group. Examples of the condensing method and eliminating method of a protecting group to be known include methods described in the following (1)-(5).
     (1) M. Bodanszky and M. A. Ondetti: Peptide synthesis, Interscience Publishers, New York (1966)   (2) Schroeder and Luebke: The Peptide, Academic Press, New York (1965)   (3) Nobuo Izumiya, et al.: Peptide Gosei-no-Kiso to Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975)   (4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977)   (5) Haruaki Yajima, ed.: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Vol. 14, peptide synthesis, published by Hirokawa Shoten.   

     After the reaction, the GIP receptor agonist peptide can be purified and isolated using conventional methods of purification, such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc., in combination thereof When the peptide obtained by the above-mentioned method is in a free form, it can be converted to a suitable salt by a known method; conversely, when the peptide is obtained in the form of a salt, the salt can be converted to a free form or other salt by a known method. 
     The starting compound may also be a salt. Examples of such salt include those exemplified as salts of the exemplified selective GIPr agonists mentioned bellow. 
     For condensation of protected amino acid or peptide, various activation reagents usable for peptide synthesis can be used, which include trisphosphonium salts, tetramethyluronium salts, carbodiimides and the like. Examples of the trisphosphonium salt include benzotriazol-1-yloxytris(pyrrolizino)phosphoniumhexafluorophosphate (PyBOP), bromotris(pyrrolizino)phosphoniumhexafluorophosphate (PyBroP), 7-azabenzotriazol-1-yloxytris(pyrrolizino)phosphoniumhexafluorophosphate (PyAOP), examples of the tetramethyluronium salt include 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU), 2-(5-norbornane-2,3-dicarboxyimide)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TNTU), O—(N-succimidyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TSTU), and examples of the carbodiimide include N,N′-Dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIPCDI), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI⋅HCl) and the like. For condensation using these, addition of a racemization inhibitor [e.g., N-hydroxy-5-norbornene-2,3-dicarboxylic imide (HONB), 1-hydroxybenzotriazole (HOBt), 1-Hydroxy-7-azabenzotriazole (HOAt), 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) etc.] is example. A solvent to be used for the condensation can be appropriately selected from those known to be usable for peptide condensation reaction. For example, acid amides such as anhydrous or water-containing N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and the like, halogenated hydrocarbons such as methylene chloride, chloroform and the like, alcohols such as trifluoroethanol, phenol and the like, sulfoxides such as dimethylsulfoxide and the like, tertiary amines such as pyridine and the like, ethers such as dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, esters such as methyl acetate, ethyl acetate and the like, an appropriate mixture of these and the like can be used. Reaction temperature is appropriately selected from the range known to be usable for peptide binding reactions, and is normally selected from the range of about −20° C. to 90° C. An activated amino acid derivative is normally used from 1.5 to 6 times in excess. In solid phase synthesis, when a test using the ninhydrin reaction reveals that the condensation is insufficient, sufficient condensation can be conducted by repeating the condensation reaction without elimination of protecting groups. If the condensation is yet insufficient even after repeating the reaction, unreacted amino acids can be acylated with acetic anhydride, acetylimidazole or the like so that an influence on the subsequent reactions can be avoided. 
     Examples of the protecting groups for the amino groups of the starting amino acid include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl (Cl—Z), 2-bromobenzyloxycarbonyl (Br—Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulphenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl and the like. 
     Examples of the carboxyl-protecting group for the starting amino acid include aryl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl and benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like, in addition to the above-mentioned C 1-6  alkyl group, C 3-10  cycloalkyl group, C 7-14  aralkyl group. 
     The hydroxyl group of serine or threonine can be protected, for example, by esterification or etherification. Examples of the group suitable for the esterification include lower (C 2-4 ) alkanoyl groups such as an acetyl group and the like, aroyl groups such as a benzoyl group and the like, and the like, and a group derived from an organic acid and the like. In addition, examples of the group suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl(Bu t ), trityl (Trt) and the like. 
     Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br—Z, tert-butyl and the like. 
     Examples of the protecting group for the imidazole of histidine include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc and the like. 
     Examples of the protecting group for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8-pentamethylchromane-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO 2  and the like. 
     Examples of the protecting group for a side chain amino group of lysine include Z, Cl—Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde) and the like. 
     Examples of the protecting group for indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr and the like. 
     Examples of the protecting group for asparagine and glutamine include Trt, xanthyl (Xan), 4,4′-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and the like. 
     Examples of activated carboxyl groups in the starting material include corresponding acid anhydride, azide, active esters [ester with alcohol (e.g., pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethylalcohol, paranitrophenol, HONB, N-hydroxysuccimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole(HOAt))] and the like. Examples of the activated amino group in the starting material include corresponding phosphorous amide. 
     Examples of the method for removing (eliminating) a protecting group include a catalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd-black or Pd-carbon; an acid treatment using anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris(trifluoro)boric acid, boron tribromide, or a mixture solution thereof; a base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine or the like; and reduction with sodium in liquid ammonia, and the like. The elimination reaction by the above-described acid treatment is generally carried out at a temperature of −20° C. to 40° C.; the acid treatment is efficiently conducted by adding a cation scavenger such as anisole, phenol, thioanisole, metacresol and paracresol; dimethylsulfide, 1,4-butanedithiol, 1,2-ethanedithiol, triisopropylsilane and the like. Also, a 2,4-dinitrophenyl group used as a protecting group of the imidazole of histidine is removed by thiophenol treatment; a formyl group used as a protecting group of the indole of tryptophan is removed by deprotection by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, or the like, as well as by alkali treatment with dilute sodium hydroxide, dilute ammonia, or the like. 
     Protection of a functional group that should not be involved in the reaction of a starting material and a protecting group, elimination of the protecting group, activation of a functional group involved in the reaction and the like can be appropriately selected from known protecting groups and known means. 
     In a method of preparing an amide of the peptide, it is formed by a solid phase synthesis using a resin for amide synthesis, or the α-carboxyl group of the carboxy terminal amino acid is amidated, and a peptide chain is elongated to a desired chain length toward the amino group side, thereafter a peptide wherein the protecting group for the N-terminal α-amino group of the peptide chain only removed and a peptide wherein the protecting group for the C-terminal carboxyl group only removed of the peptide chain are prepared, and the both peptides are condensed in a mixed solvent described above. For details about the condensation reaction, the same as above applies. After the protected peptide obtained by the condensation is purified, all protecting groups can be removed by the above-described method to yield a desired crude polypeptide. By purifying this crude peptide using various publicly known means of purification, and freeze-drying the main fraction, a desired amide of the peptide can be prepared. 
     When the GIP receptor agonist peptide is present as a configurational isomer such as enantiomer, diastereomer etc., a conformer or the like, they are also encompassed within the description of a GIP receptor agonist peptide and each can be isolated by a means known per se or the above separation and purification methods on demand. In addition, when the GIP receptor agonist peptide is in the form of a racemate, it can be separated into S- and R-forms by conventional optical resolution. 
     When a GIP receptor agonist peptide includes stereoisomers, both the isomers alone and mixtures of each isomers are also encompassed within the meaning of a GIP receptor agonist peptide. A GIP receptor agonist peptide can be chemically modified according to a method known per se and using substituent and polyethylene glycol. For example, a chemically modified GIP receptor agonist peptide can be produced by introducing substituent and/or conjugatedly binding polyethylene glycol to Cys residue, Asp residue, Glu residue, Lys residue and the like of a GIP receptor agonist peptide. Additionally, there may be a linker structure between the amino acid of the GIP receptor agonist peptide and substituent and polyethylene glycol. 
     A GIP receptor agonist peptide modified by a substituent and/or polyethylene glycol (PEG) produces for example, one or more effects related to promoting the biological activity, prolonging the blood circulation time, resistance to elimination, reducing the immunogenicity, enhancing the solubility, and enhancing the resistance to metabolism, of a therapeutically and diagnostically important peptide. 
     The molecular weight of PEG is not particularly limited and is normally about 1 K to about 1000 K daltons, or about 10 K to about 100 K daltons, or about 20 K to about 60 K Daltons. 
     Modifying a selective GIPr agonist of the present disclosure by adding an (R) substituent can be conducted by introducing the (R) substituent based on known oxidation reaction and reduction reaction. 
     A method well known in the art can be used as a method for modifying a GIP receptor agonist peptide by PEG, and, for example, in addition to the exemplary methods listed above, the methods described below can be used. 
     (1) A PEGylating reagent having an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.) is bound to an amino group of the GIP receptor agonist peptide.
 
(2) A PEGylating reagent having an aldehyde (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.) is bound to the amino group of the GIP receptor agonist peptide.
 
(3) A divalent cross-linking reagent (e.g., GMBS (Dojindo Laboratories), EMCS (Dojindo Laboratories), KMUS (Dojindo Laboratories), SMCC (Pierce)) is bound to an amino acid, (for example, a Lys and/or a Cys), of the GIP receptor agonist peptide, to which a PEGylating reagent having a thiol group (e.g., SUNBRIGHT ME-300-SH (trade name), NOF Corp.) is then bound.
 
(4) A thiol group is introduced to a GIP receptor agonist peptide through an SH-introducing agent (e.g., D-cysteine residue, L-cysteine residue, Traut&#39;s reagent), and this thiol group is reacted with a PEGylating reagent having a maleimide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.).
 
(5) A thiol group is introduced to GIP receptor agonist peptide through an SH-introducing agent (e.g., D-cysteine residue, L-cysteine residue, Traut&#39;s reagent), and this thiol group is reacted with a PEGylating reagent having an iodoacetamide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.).
 
(6) A ω-aminocarboxylic acid, an α-amino acid or the like is introduced as a linker to the N-terminal amino group of a GIP receptor agonist peptide, and an amino group derived from this linker is reacted with a PEGylating reagent having an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.).
 
(7) A ω-aminocarboxylic acid, an α-amino acid or the like is introduced as a linker to the N-terminal amino group of a GIP receptor agonist peptide, and an amino group derived from this linker is reacted with a PEGylating reagent having an aldehyde group (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.).
 
     In addition, the GIP receptor agonist peptide may be a solvate (e.g., hydrate) or a non-solvate (e.g., non-hydrate). 
     The GIP receptor agonist peptide may be labeled with an isotope (e.g.,  3 H,  14 C,  35 S,  125 I) or the like. 
     Furthermore, GIP receptor agonist peptide may be a deuterium conversion form wherein  1 H is converted to  2 H(D). 
     In some embodiments, a GIP receptor agonist peptide labeled with or substituted with an isotope can be used as, for example, a tracer (PET tracer) for use in Positron Emission Tomography (PET), and is useful in the fields of medical diagnosis and the like. 
     For the GIP receptor agonist peptide mentioned herein, the left end is the N-terminal (amino terminal) and the right end is the C-terminal (carboxyl terminal) in accordance with the conventional peptide marking. The C-terminal of peptide may be any of an amide (—CONH 2 ), a carboxyl group (—COOH), a carboxylate (—COO—), an alkylamide (—CONHR a ), and an ester (—COOR a ). In some embodiments, the C-terminal is amide (—CONH 2 ). 
     A GIP receptor agonist peptide of the present disclosure may be in a salt form. Examples of such salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like. 
     Examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. 
     Examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like. 
     Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. 
     Examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. 
     Examples of the salt with basic amino acid include salts with arginine, lysine, omithine and the like. Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. 
     Among the above-mentioned salts, a pharmaceutically acceptable salt is of interest. For example, when a compound has an acidic functional group, an inorganic salt such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, for example, a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or a salt with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like are some examples. 
     In some embodiments, the GIP receptor agonist peptide may be synthesized and/or used in a prodrug form to treat or prevent a disease of the present disclosure, for example, diabetes, obesity and/or emesis. A prodrug means a compound which is converted to a GIP receptor agonist peptide with a reaction due to an enzyme, gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to a GIP receptor agonist peptide with oxidation, reduction, hydrolysis, etc. according to an enzyme; a polypeptide which is converted to GIP receptor agonist peptide by hydrolysis etc. due to gastric acid, etc. 
     Examples of a prodrug of a GIP receptor agonist peptide may include a compound wherein an amino group of a GIP receptor agonist peptide is acylated, alkylated or phosphorylated (e.g., compound wherein amino group of a GIP receptor agonist peptide is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound wherein a hydroxy group of a GIP receptor agonist peptide is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of a GIP receptor agonist peptide is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); a compound wherein a carboxy group of a GIP receptor agonist peptide is esterified or amidated (e.g., a compound wherein a carboxy group of a GIP receptor agonist peptide is C 1-6  alkyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated) and the like. Among others, a compound wherein a carboxy group of a GIP receptor agonist peptide is esterified with C 1-6  alkyl such as methyl, ethyl, tert-butyl or the like may be used. These compounds, peptides and polypeptides can be produced from a GIP receptor agonist peptide by a method known per se. 
     A prodrug of a GIP receptor agonist peptide may also be one which is converted into a GIP receptor agonist peptide under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990). 
     In the present specification, the prodrug may form a salt. Examples of such a salt include those exemplified as the salt of a GIP receptor agonist peptide. 
     In some embodiments, a GIP receptor agonist peptide of the present disclosure may be synthesized and/or used as a crystal. Crystals having a singular crystal form or a mixture of plural crystal forms are also encompassed by the examples of GIP receptor agonist peptides. Crystals can be produced by crystallizing a GIP receptor agonist peptide according to a crystallization method known per se. 
     In addition, a GIP receptor agonist peptide may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, the cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, hygroscopicity, solubility, stability etc.). The cocrystal and cocrystal salt can be produced by cocrystallization known per se. 
     The crystal of a GIP receptor agonist peptide of the present disclosure is superior in physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and thus it is extremely useful as a medicament. 
     In some embodiments, a GIP receptor agonist peptide and/or a prodrug thereof (hereinafter to be sometimes abbreviated as a GIP receptor agonist peptide of the present disclosure) have a GIP receptor activating action, and may have selectivity as agonists of the GIP receptor over other receptors such as the GLP1R. The compounds of the present disclosure have a high GIP receptor selective activation action in vivo. 
     C. METHODS OF PROPHYLAXIS AND TREATMENT OF GIP MEDIATED CONDITIONS, DISEASES, AND DISORDERS 
     GIP is a gastrointestinal hormone called incretin and has a promoting action on insulin secretion from the pancreas. Incretin is closely related to glucose metabolism and thus the compound having a GIP receptor activation action is useful for preventing and treating symptoms related to abnormal glucose metabolism including diabetes and obesity. Additionally, the compounds of the present disclosure have a GIP receptor selective activation action and suppresses vomiting by activating GABAergic neurons in the area postrema. 
     More specifically, the GIP receptor agonist peptides of the present disclosure have a hypoglycemic action, an antiemetic action, and the like. 
     The GIP receptor agonist peptides of the present disclosure have a high chemical stability and excellent persistence of the effects in vivo. 
     The GIP receptor agonist peptides of the present disclosure may be used as a GIP receptor activator. 
     In the present disclosure, the GIP receptor activator (GIP receptor agonist) means an agent having a GIP receptor activation action. Additionally, the GIP receptor selective activator (GIP receptor peptide agonist) specifically means an agent having an EC 50  for the GIP receptor of 1/10 or less, or 1/100 or less, or 1/1000 or less, or 1/10000 or less, times the EC 50  for the GLP-1 receptor. 
     The GIP receptor agonist peptides of the present disclosure is low in its toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, carcinogenicity), shows a few side effects, and can be safely administered to a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) as an agent for the prophylaxis or treatment of various diseases mentioned below and the like. 
     The GIP receptor agonist peptides of the present disclosure can be used as an agent for the treatment or prophylaxis of various diseases including diabetes and obesity, by virtue of the above-mentioned activating action on GIP receptors. The GIP receptor agonist peptides of the present disclosure can be used as an agent for the prophylaxis or treatment of, for example, symptomatic obesity, obesity based on simple obesity, disease state or disease associated with obesity, eating disorder, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), hypertension, cardiac failure, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (disease states having 3 or more selected from hypertriglyceridemia, (TG), low HDL cholesterol(HDL-C)emia, hypertension, abdominal obesity and impaired glucose tolerance), sarcopenia and the like. 
     Examples of the symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea (SU) agent, β-blocker-induced obesity) and the like. 
     Examples of the disease state or disease associated with obesity include glucose tolerance disorders, diabetes (e.g., type 2 diabetes (T2DM), obese diabetes), lipid metabolism abnormality (synonymous with the above-mentioned hyperlipidemia), hypertension, cardiac failure, hyperuricemia.gout, fatty liver (including non-alcoholic steato-hepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (brain thrombosis, transient cerebral ischemic attack), bone/articular disease (knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome/Pickwick syndrome, menstrual disorder (abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), metabolic syndrome and the like. 
     New diagnostic criteria were reported by The Japan Diabetes Society in 1999 about the diagnostic criteria of diabetes. 
     According to this report, diabetes refers to a state that meets any of a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg/dl or more, a 2-hr value (glucose concentration in venous plasma) of 200 mg/dl or more in the 75 g oral glucose tolerance test (75 g OGTT), and a casual blood glucose level (glucose concentration in venous plasma) of 200 mg/dl or more. Also, a state that does not apply to the above-mentioned diabetes, and is not a state exhibiting “a fasting blood glucose level (glucose concentration in venous plasma) less than 110 mg/dl or a 2-hr value (glucose concentration in venous plasma) less than 140 mg/dl in the 75 g oral glucose tolerance test (75 g OGTT)” (normal type) is called “borderline type”. 
     Moreover, new diagnostic criteria were reported by American Diabetes Association (ADA) in 1997 and by World Health Organization (WHO) in 1998 about the diagnostic criteria of diabetes. 
     According to these reports, diabetes refers to a state that meets a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg/dl or more and a 2-hr value (glucose concentration in venous plasma) of 200 mg/dl or more in the 75 g oral glucose tolerance test. 
     According to the above-mentioned reports, impaired glucose tolerance refers to a state that meets a fasting blood glucose level (glucose concentration in venous plasma) less than 126 mg/dl and a 2-hr value (glucose concentration in venous plasma) of 140 mg/dl or more and less than 200 mg/dl in the 75 g oral glucose tolerance test. According to the report of ADA, a state exhibiting a fasting blood glucose level (glucose concentration in venous plasma) of 110 mg/dl or more and less than 126 mg/dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, a state of the IFG (Impaired Fasting Glucose) exhibiting a 2-hr value (glucose concentration in venous plasma) less than 140 mg/dl in the 75 g oral glucose tolerance test is called IFG (Impaired Fasting Glycemia). 
     The GIP receptor agonist peptides of the present disclosure may also be used as an agent for the prophylaxis or treatment of diabetes determined according to the above-mentioned new diagnostic criteria, borderline type diabetes, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia). Moreover, the GIP receptor agonist peptides of the present disclosure can prevent progress of borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) into diabetes. 
     The GIP receptor agonist peptides of the present disclosure are also useful as an agent for the prophylaxis or treatment of metabolic syndrome. The incidence of cardiovascular disease is significantly high in metabolic syndrome patients, compared with patients with a single lifestyle-related disease. Thus, the prophylaxis or treatment of metabolic syndrome is exceedingly important for preventing cardiovascular disease. 
     The diagnostic criteria of metabolic syndrome were announced by WHO in 1999 and by NCEP in 2001. According to the diagnostic criteria of WHO, an individual having hyperinsulinemia or abnormal glucose tolerance as a requirement and two or more of visceral obesity, dyslipidemia (high TG or low HDL) and hypertension is diagnosed as having metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the diagnostic criteria of the Adult Treatment Panel III of the National Cholesterol Education Program (guideline of ischemic heart disease) in USA, an individual having three or more of visceral obesity, hypertriglyceridemia, low HDL-cholesterolemia, hypertension and abnormal glucose tolerance is diagnosed as having metabolic syndrome (National Cholesterol Education Program: Executive Summary of the Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001). 
     More specifically, the GIP receptor agonist peptides of the present disclosure have an antiemetic action, and may inhibit or reduce the number and severity of the occurrence of nausea, and/or vomiting when associated with various stimuli disclosed herein, for example, when a subject has cyclic vomiting syndrome or is administered a chemotherapeutic drug, for example, a chemotherapeutic drug with emetic potential, such as platinum based chemotherapeutics such as cisplatin, oxaliplatin, and carboplatin; irinotecan and other topo isomerase inhibitors used in the treatment of cancer. The GIP receptor agonist peptides of the present disclosure have a high chemical stability and excellent persistence of the effects in vivo. 
     The GIP receptor agonist peptides of the present disclosure may be used as a GIP receptor activator. In the present disclosure, the GIP receptor activator (GIP receptor agonist) means an agent having a GIP receptor activation action. Additionally, the GIP receptor selective activator (i.e. a GIP receptor agonist as used herein) specifically means an agent having an EC 50  for the GIP receptor of 1/1000 or less, or 1/10000 or less, times the EC 50  for the GLP-1 receptor, or in other words the ratio of EC 50  GLP1R/EC 50  GIPR is greater than 10, greater than 100, or greater than 1,000, or greater than 10,000, or from 100 to 1,000,000 or more. 
     The GIP receptor agonist peptides of the present disclosure have low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, carcinogenicity), shows a few side effects, and can be safely administered to a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) as an agent for the prophylaxis or treatment of emesis. 
     “Treatment,” in the context of treating emesis by administering at least one of the GIP receptor agonist peptides disclosed herein, includes both prophylactic treatment and the treatment of emesis after a subject experiences emesis. Prophylactic treatment includes administration of a GIP receptor agonist peptide before a subject experiences emesis, such as when the subject experiences nausea, as well as administration of the GIP receptor agonist peptide before the subject is exposed to a substance, agent, or event, or before the subject contracts a condition, which results in or is likely to result in the subject experiencing emesis. As used herein, “therapeutically effective amount” refers to an amount of the GIP receptor agonist peptide sufficient to elicit the desired biological response. In the present disclosure, the desired biological response is treating and/or preventing an abnormal glucose metabolism in a subject, for example, in a subject in need thereof, including diabetes and obesity, or the prevention and/or treatment of emesis in a subject in need thereof. 
     The compound of the present invention can also be used for secondary prevention or suppression of progression of the above-mentioned various diseases (e.g., cardiovascular events such as myocardial infarction and the like). In addition, the compound of the present invention is also useful as a feeding suppressant and a weight reducing agent. The compound of the present invention can also be used in combination with a diet therapy (e.g., diet therapy for diabetes), and an exercise therapy. The GIP receptor agonist peptides of the present disclosure can be used to treat or prevent diabetes and/or obesity, a pathophysiological condition related to diabetes and/or obesity, emesis, for example, when a subject experiences or is about to experience emesis, such as nausea and/or vomiting. In various embodiments, the subject, for example, a mammal, for example, humans, non-human primates, apes, monkeys, laboratory mammals for example, mice, rats, rabbits, guinea-pigs, ferrets, domesticated mammals, such as companion mammals, dogs, cats and horses, and farm mammals, such as cattle, pigs, sheep and goats purely as examples, but not intended to be an exhaustive list, may be treated with a GIP receptor agonist peptide of the present disclosure. In each of these cases, the methods of the present disclosure are provided to treat or prevent diabetes, obesity, or emesis in a subject in need thereof, to reduce or inhibit diabetes, obesity, or emesis, to reduce or inhibit a symptom associated with diabetes, obesity, or emesis, or to reduce or inhibit a pathological condition or symptom associated with diabetes, obesity, or emesis, for example, nausea and/or vomiting. 
     In order to prevent or treat emesis, an effective amount of one or more of the present compounds in a pharmaceutical composition is administered once per day to a subject/patient (used interchangeably herein) in need thereof A subject is determined to be in need of treatment with the present GIP receptor agonist peptide either through observation of vomiting by the subject, or through a subject&#39;s self-reporting of emesis (in the case of a human subject). A patient is determined to be in need of preventative therapy by assessing that the patient is at risk of experiencing emesis due to another medical condition or due to exposure to an agent known to be associated with emesis, such as an infection by a virus or bacteria or chemical agent or radiation. 
     The present GIP receptor agonist peptides are beneficial in the therapy of acute, delayed or anticipatory emesis, including emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders (e.g. motion sickness, vertigo, dizziness and Meniere&#39;s disease), surgery, pain, opioid use and withdrawal, migraine, and variations in intracranial pressure. The uses of this invention are of benefit in the therapy of emesis induced by radiation, for example during the treatment of cancer, or radiation sickness, and in the treatment of post-operative nausea and vomiting. Most especially, use of the invention is beneficial in the therapy of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy, emesis induced by other pharmacological agents, for example, alpha-2 adrenoceptor antagonists, such as yohimbine, MK-912 and MK-467, and type IV cyclic nucleotide phosphodiesterase (PDE4) inhibitors, such as RS14203, CT-2450 and rolipram. 
     Examples of chemotherapeutic agents are described, for example, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, ed. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Fla., USA, 1991, pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, cyclophosphamide, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), irinotecan, and other topoisomerase inhibitors, lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel and chlorambucil (R. J. Gralle et al. in Cancer Treatment Reports, 1984, 68, 163-172). Emesis due to other chemical agents, such as the toxins soman or sarin, or opiod drug usage and/or withdrawal, e.g. morphine, heroin, oxycodone, and the like can also be prevented and/or treated. 
     The present compounds are administered to a patient in a quantity sufficient to treat or prevent the symptoms and/or underlying etiology associated with emesis in the patient. In a preferred embodiment, the GIP receptor agonist peptides are administered prior to administration of an agent which is likely to cause emesis, such as one or more of the chemotherapeutic agents described above. The present GIP receptor agonist peptides can also be administered in combination with such agents, either in physical combination or in combined therapy through the administration of the present compounds and agents in succession (in any order). Although the present invention is useful in any mammal suffering from emesis, a preferred subject is a human. 
     In some embodiments, the selective GIPr agonists of the present disclosure may be administered to treat emesis when a subject is concomitantly being treated for diabetes and/or obesity. Several known anti-diabetic medicaments are known for causing emesis, for example, Metformin (Glucophage, Glumetza, others), sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. In some embodiments, methods for treating emesis in a subject, for example in a subject in need thereof, may include administering an effective amount of a GIP receptor agonist peptide to a subject that does not have type-2 diabetes mellitus or a subject that is not taking a medicament to treat type-2 diabetes mellitus while experiencing emesis. 
     Nausea is a subjective unpleasant feeling in the back of one&#39;s throat and stomach that may lead to vomiting. There are many words that describe nausea including, but not limited to: sick to my stomach, queasy, or upset stomach. Nausea can have other symptoms that happen at the same time, such as increased saliva (spit), dizziness, light-headedness, trouble swallowing, skin temperature changes, and a fast heart rate. Vomiting is also described as “throwing up.” When one vomits, one&#39;s stomach muscles contract (squeeze) and push the contents of one&#39;s stomach out through their mouth. One might or might not feel nauseated. Retching is when one tries to vomit without bringing anything up from one&#39;s stomach. Other words used to describe retching are gagging or dry heaves. Nausea and vomiting often happen at the same time, but they can be 2 different conditions that may be mutually exclusive or mutually associated. Some chemotherapy drugs are more likely to cause nausea and vomiting than others. Doctors classify chemotherapy drugs according to their emetogenic potential (how likely the drug will cause nausea or vomiting) as high, moderate, low, or minimal risk. 
     In various embodiments, the GIPR agonist peptide compounds may be dosed once per day to provide treatment and prophylactic treatment against emesis and emesis related symptoms. The peptide compounds of the present disclosure may be used to preferentially treat cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV). Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder that is being increasingly recognized in adults. It is characterized by episodic nausea and vomiting and is associated with significant morbidity. 
     An estimated 80% of patients with cancer will experience chemotherapy-induced nausea and vomiting (CINV). The term CINV includes emesis and nausea, which can involve a loss of appetite and result in decreased oral intake of fluids and calories. Five different types of CINV have been defined and include acute, delayed, breakthrough, anticipatory, and refractory CINV. 
     Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting or retching experienced by a patient in the Post Anesthesia Care Unit (PACU) or 24-hours following a surgical procedure. It is an unpleasant complication that affects about 10% of the population undergoing general anaesthesia each year. 
     In an exemplary embodiment, the present disclosure provides for the prophylactic treatment or maintenance therapy for cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV), comprising administering one or more GIPR agonist peptide compounds of the present disclosure, for example, a GIPR agonist peptide compound selected from compound 17, 25, 21, 48, 142, 14 and 20, in a therapeutically effective amount to a subject in need thereof. 
     The GIP receptor agonist peptides of the present disclosure may be used as a preventive/therapeutic agent, ie. prophylactic treatment or maintenance therapy for vomiting and/or nausea caused, for example, by clinical pathological conditions or causes described in the following 
     The GIP receptor agonist peptides of the present disclosure may be used as a preventive/therapeutic agent for vomiting and/or nausea caused, for example, by clinical pathological conditions or causes described in the following (1) to (10). Additionally, the GIP receptor agonist peptide of the present disclosure may be used as a preventive/therapeutic agent for chronic unexplained nausea and vomiting. The vomiting or nausea also includes imminent unpleasant sensations of wanting to eject the contents of the stomach through the mouth such as feeling queasy and retching, and may also be accompanied by autonomic symptoms such as facial pallor, cold sweat, salivary secretion, tachycardia, and diarrhea. The vomiting also includes acute vomiting, protracted vomiting, and anticipatory vomiting. 
     (1) Diseases accompanied by vomiting or nausea such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, chronic intestinal pseudo-obstruction, functional dyspepsia, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hepatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness);
 
(2) Vomiting and/or nausea induced by chemotherapeutic drugs such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome;
 
(3) Vomiting or nausea caused by radiation sickness or radiation therapy for the chest, the abdomen, or the like used to treat cancers;
 
(4) Vomiting or nausea caused by a poisonous substance or a toxin;
 
(5) Vomiting and nausea caused by pregnancy including hyperemesis gravidarium; and
 
(6) Vomiting and nausea caused by a vestibular disorder such as motion sickness or dizziness
 
(7) Opioid withdrawal;
 
(8) Vomiting and nausea caused by post-operative nausea and vomiting;
 
(9) A vestibular disorder such as motion sickness or dizziness; and
 
(10) A physical injury causing local, systemic, acute or chronic pain.
 
     These causes of emesis, or nausea, or vomiting are not meant to be exhaustive. Other conditions, activities, side effects may cause emesis, for example, nausea and/or vomiting. Nausea can be measured in ways known to the art, such as through the use of a visual analog scale (VAS). 
     The compound of the present invention can also be used for secondary prevention or suppression of progression of the above-mentioned various diseases (e.g., cardiovascular events such as myocardial infarction and the like). In addition, the compound of the present invention is also useful as a feeding suppressant and a weight reducing agent. The compound of the present invention can also be used in combination with a diet therapy (e.g., diet therapy for diabetes), and an exercise therapy. 
     D. FORMULATIONS 
     A medicament containing a GIP receptor agonist peptide of the present disclosure shows low toxicity and is obtained using the compound of the present disclosure alone or in admixture with a pharmacologically acceptable carrier according to a method known per se (e.g., the method described in the Japanese Pharmacopoeia) generally used as production methods of pharmaceutical preparations, and safely administered orally or parenterally (e.g., topically, rectally, intravenously administered) as a pharmaceutical preparation, for example, tablets (inclusive of sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), powders, granules, capsules (inclusive of soft capsules, microcapsules), liquids, troches, syrups, emulsions, suspensions, injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections etc.), external preparations (e.g., transnasal preparations, dermal preparations, ointments), suppository (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), transfusions and the like. 
     These preparations may be controlled release preparations such as a rapid release preparation, a sustained release preparation and the like (e.g., a sustained release microcapsule). The content of the compound of the present disclosure in a pharmaceutical preparation is about 0.01-about 100 wt % of the whole preparation. 
     The above-mentioned pharmaceutically acceptable carrier may be exemplified by various organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, lubricant, binding agent and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations. Further, if necessary, general additives such as preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be also used appropriately in a suitable amount. 
     Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. 
     Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. 
     Examples of the binding agent include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like. 
     Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like. 
     Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like. 
     Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. 
     Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like. 
     Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. 
     Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like. 
     Examples of the soothing agent include benzyl alcohol and the like. 
     Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. 
     Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like. 
     Examples of the colorant include water-soluble food coal tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and the like), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble Food coal tar dyes), natural dyes (e.g., β-carotene, chlorophyll, ferric oxide red) and the like. 
     Examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like. 
     Examples of the adsorbing include porous starch, calcium silicate (trade name: Florite RE), magnesium alumino metasilicate (trade name: Neusilin) and light anhydrous silicic acid (trade name: Sylysia). 
     Examples of the wetting agent include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. 
     During production of an oral preparation, coating may be applied as necessary for the purpose of masking of taste, enteric property or durability. 
     Examples of the coating base to be used for coating include sugar coating base, aqueous film coating base, enteric film coating base and sustained-release film coating base. 
     As the sugar coating base, sucrose is used. Moreover, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination. 
     Examples of the aqueous film coating base include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc. 
     Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and naturally occurring substances such as shellac etc. 
     Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] etc. 
     The above-mentioned coating bases may be used after mixing with two or more kinds thereof at appropriate ratios. For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used. 
     E. ADMINISTRATION 
     The therapeutically effective amount or dose of a composition or medicament containing a GIP receptor agonist peptide to be administered to a subject will depend on the age, sex and weight of the patient, and the current medical condition of the patient. The skilled artisan will be able to determine appropriate dosages depending on these and other factors to achieve the desired biological response. 
     The dosage of the GIP receptor agonist peptide of the present disclosure is appropriately determined according to the subject of administration, symptom, administration method and the like. For example, when the GIP receptor agonist peptide of the present disclosure is administered orally to a subject prior to engaging in an act that will likely cause emesis or after the onset of emesis in a human subject (body weight of approximately 60 kg), the daily dose of the compound of the present disclosure is about 0.01 to 100 mg, or about 1.0 to 50 mg, or about 1.0 to 20 mg. When the compound of the present disclosure is administered parenterally to an obesity or diabetes patient or a gastroparesis (body weight 60 kg), the daily dose of the compound of the present disclosure is about 0.001 to 30 mg, or about 0.01 to 20 mg, or about 0.1 to 10 mg. These amounts can be administered in about 1 to several portions a day. In some embodiments, a therapeutically effective amount of a GIP receptor agonist peptide to prevent and/or treat emesis in a subject in need thereof may range from about 0.01 to 0.5 mg/kg/day, 0.1 to 5 mg/kg/day, 5 to 10 mg/kg/day, 10 to 20 mg/kg/day, 20 to 50 mg/kg/day, 10 to 100 mg/kg/day, 10 to 120 mg/kg/day, 50 to 100 mg/kg/day, 100 to 200 mg/kg/day, 200 to 300 mg/kg/day, 300 to 400 mg/kg/day, 400 to 500 mg/kg/day, 500 to 600 mg/kg/day, 600 to 700 mg/kg/day, 700 to 800 mg/kg/day, 800 to 900 mg/kg/day or 900 to 1000 mg/kg/day. 
     The GIP receptor agonist peptide of the present disclosure can be administered, for example, once per day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, twice per week, every other week, every 3 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months or every 6 months. In some embodiments, the GIP receptor agonist peptide of the present disclosure can be administered to the subject 1 times per day, QD, or 1-7 times per week, for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years. 
     The GIP receptor agonist peptide of the present disclosure can be used in combination with another drug that does not adversely influence the GIP receptor agonist peptide of the present disclosure, for the purpose of, for example, promoting the action (antiemetic action) of the GIP receptor agonist peptide of the present disclosure, reducing the dose of the GIP receptor agonist peptide of the present disclosure, and the like. 
     Examples of a drug that can be used in combination with the GIP receptor agonist peptide of the present disclosure (hereinafter sometimes to be abbreviated as a concomitant drug) include anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, therapeutic agents for osteoporosis, vitamins, antidementia drugs, erectile dysfunction drugs, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic agents for dysuria, central D2 receptor antagonists, prokinetic agents, antihistamines, muscarine receptor antagonists, serotonin 5HT3 receptor antagonists, somatostatin analogues, corticosteroids, benzodiazepine anxiolytics, NK-1 receptor antagonists, hypercalcemia therapeutic drug and the like. Specific examples of the concomitant drug include those mentioned below. 
     Examples of the anti-obesity agent include monoamine uptake inhibitors (e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulator, GABA modulator (e.g., topiramate), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelinacylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 110-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), 03 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturated enzyme inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), Na-glucose cotransporter inhibitors (e.g., JNJ-28431754, remogliflozin), NFx inhibitory (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, Trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., AZD-1656), leptin, leptin derivatives (e.g., metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using  Escherichia coli  or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), GLP-1 receptor agonist, GLP-1 receptor/GIP receptor coagonist, glucagon receptor/GLP-1 receptor/GIP receptor triagonist, and the like. 
     Here, as the therapeutic agent for diabetes, for example, insulin preparations (e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using  Escherichia coli  or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (e.g., hydrochloride), rosiglitazone or a salt thereof (e.g., maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compound described in WO007/013694, WO2007/018314, WO2008/093639 or WO2008/099794), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues (e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof), dipeptidyl peptidase IV inhibitors (e.g., Alogliptin or a salt thereof (e.g., benzoate), Vildagliptin, Sitagliptin, Saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, Trelagliptin or a salt thereof (e.g., succinate)), 03 agonists (e.g., N-5984), GPR40 agonists (e.g., Fasiglifam or a hydrate thereof, compound described in WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 or WO2008/001931), SGLT2 (sodium-glucose cotransporter 2) inhibitors (e.g., Dapagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitors, 11-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, INCB-13739), adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868), leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (e.g., Piragliatin, AZD1656, AZD6370, TTP-355, compound described in WO006/112549, WO007/028135, WO008/047821, WO008/050821, WO008/136428 or WO008/156757), GPR119 agonists (e.g., PSN821, MBX-2982, APD597), FGF21, FGF analogue, ACC2 inhibitors, GLP-1 receptor agonist, GLP-1 receptor/GIP receptor coagonist, glucagon receptor/GLP-1 receptor/GIP receptor triagonist, and the like can be mentioned. 
     As the therapeutic agent for diabetic complications may include, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidorestat), neurotrophic factor and increasing agents thereof (e.g., NGF, NT-3, BDNF, neurotrophic production/secretion promoting agent described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compound described in WO2004/039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, Pyridorin, pyridoxamine), GABA receptor agonists (e.g., gabapentin, pregabalin), serotonin and noradrenalin reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors, GLP-1 receptor agonist, GLP-1 receptor/GIP receptor coagonist, glucagon receptor/GLP-1 receptor/GIP receptor triagonist, and the like can be mentioned. 
     As the therapeutic agent for hyperlipidemia, HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compound described in WO97/10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (e.g., colestyramine), probucol, nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), ethyl icosapentate, phytosterol (e.g., soysterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl esters 90 (ω-3-acid ethyl esters 90)) and the like can be mentioned. 
     Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine, etc.), β blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like. 
     As the diuretic, for example, xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate and the like), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, poly5thiazide, methyclothiazide and the like), antialdosterone preparations (e.g., spironolactone, triamterene and the like), carbonic anhydrase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide and the like), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. 
     Examples of the chemotherapeutic include alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), anticancer antibiotics (e.g., mitomycin, adriamycin), plant-derived anticancer agents (e.g., vincristine, vindesine, Taxol), cisplatin, carboplatin, etoposide and the like. Among others, a 5-fluorouracil derivative Furtulon or Neofurtulon or the like may be used. Also a composition comprising a GIP receptor agonist peptide of the disclosure can be administered before, after or during the administration of the following anti-cancer agents: cisplatin, carboplatin. Oxaliplatin, cyclophosphamide, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel and chlorambucil. 
     Examples of the immunotherapeutic include microbial or bacterial components (e.g., muramyl dipeptide derivative, Picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, sizofiran, Krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL)), colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin) and the like. Among others, interleukins such as IL-1, IL-2, IL-12 and the like are some examples. 
     Examples of the anti-inflammatory drug include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, indomethacin and the like. 
     As the antithrombotic agent, for example, heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), anti-thrombin drugs (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, compound described in WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or WO2005/113504), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like can be mentioned. 
     Examples of the therapeutic agent for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium and the like. 
     Examples of the vitamin include vitamin B1, vitamin B12 and the like. 
     Examples of the antidementia drug include tacrine, donepezil, rivastigmine, galanthamine and the like. 
     Examples of the erectile dysfunction drug include apomorphine, sildenafil citrate and the like. 
     Examples of the therapeutic drug for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like. 
     Examples of the therapeutic agent for dysuria include acetylcholine esterase inhibitors (e.g., distigmine) and the like. 
     Examples of the central D2 receptor antagonist include typical psychotropic drugs (prochlorperazine, haloperidol, chlorpromazine, and the like), serotonin dopamine antagonists (perospirone, risperidone, and the like), and multi-acting receptor targeted antipsychotic drugs (olanzapine and the like). 
     Examples of the prokinetic agent include peripheral D2 receptor antagonists (metoclopramide, domperidone, and the like) and 5HT4 receptor agonists (mosapride and the like). 
     Examples of the antihistamine include hydroxyzine, diphenhydramine, and chlorpheniramine. 
     Examples of the muscarinic receptor antagonist include central muscarinic receptor antagonists (scopolamine and the like) and peripheral muscarinic receptor antagonists (butylscopolamine and the like). 
     Examples of the serotonin 5HT3 receptor antagonist include granisetron, ondansetron, azasetron, indisetron, palonosetron, and ramosetron. 
     Examples of the somatostatin analogue include octreotide. 
     Examples of the corticosteroid include dexamethasone, betamethasone, and methylprednisolone. 
     Examples of the benzodiazepine anxiolytic include lorazepam and alprazolam, examples of the NK-1 receptor antagonist include aprepitant and fosaprepitant, and examples of the hypercalcemia therapeutic drug include bisphosphonate. 
     Moreover, a drug confirmed to have a cachexia-ameliorating action either in animal models or clinically, i.e., a cyclooxygenase inhibitor (e.g., indomethacin), a progesterone derivative (e.g., megestrol acetate), glucocorticoid (e.g., dexamethasone), a metoclopramide drug, a tetrahydrocannabinol drug, an agent for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, or an antibody against a cachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M or the like can also be used in combination with the compound of the present disclosure. 
     Alternatively, a glycation inhibitor (e.g., ALT-711), a nerve regeneration-promoting drug (e.g., Y-128, VX853, prosaptide), an antidepressant (e.g., desipramine, amitriptyline, imipramine), an antiepileptic drug (e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), an antiarrhythmic drug (e.g., mexiletine), an acetylcholine receptor ligand (e.g., ABT-594), an endothelin receptor antagonist (e.g., ABT-627), a monoamine uptake inhibitor (e.g., tramadol), a narcotic analgesic (e.g., morphine), a GABA receptor agonist (e.g., gabapentin, MR preparation of gabapentin), an α2 receptor agonist (e.g., clonidine), a local analgesic (e.g., capsaicin), an antianxiety drug (e.g., benzothiazepine), a phosphodiesterase inhibitor (e.g., sildenafil), a dopamine receptor agonist (e.g., apomorphine), midazolam, ketoconazole or the like may be used in combination with the compound of the present disclosure. 
     The time of administration of the GIP receptor agonist peptide of the present disclosure and that of the concomitant drug are not limited, and they may be administered simultaneously or in a staggered manner to the administration subject. 
     Examples of such administration mode include the following: 
     (1) administration of a single preparation obtained by simultaneously processing the GIP receptor agonist peptide of the present disclosure and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present disclosure and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, or in the reverse order) and the like. 
     The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations. The mixing ratio of the GIP receptor agonist peptide of the present disclosure and a concomitant drug can be appropriately determined depending on the administration subject, symptom, administration method, target disease, combination and the like. When the subject of administration is human, for example, a concomitant drug can be used in 0.01-100 parts by weight relative to 1 part by weight of the GIP receptor agonist peptide of the present disclosure. 
     By combining the GIP receptor agonist peptide of the present disclosure and concomitant drug: (1) the dose of the GIP receptor agonist peptide of the present disclosure or a concomitant drug can be reduced as compared to single administration of the GIP receptor agonist peptide of the present disclosure or a concomitant drug, 
     (2) the drug to be used in combination with the GIP receptor agonist peptide of the present disclosure can be selected depending on the condition of patients (mild, severe and the like), 
     (3) the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from those of the GIP receptor agonist peptide of the present disclosure, 
     (4) a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from those of the GIP receptor agonist peptide of the present disclosure, and 
     (5) a synergistic effect can be afforded by a combined use of the GIP receptor agonist peptide of the present disclosure and a concomitant drug, and the like, can be achieved. 
     F. EXAMPLES 
     The abbreviations used in the present specification mean the following (Table 2). A hyphen in terms such as α-MePhe and the like as described herein may be omitted, and the event of omission also represents the same meaning. 
     In the amino acid sequences used in the present specification, the left terminal represents N terminal and the right terminal represents C terminal. 
     
       
         
           
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Commonly used abbreviations in the present disclosure. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Ac 
                 acetyl 
               
               
                 Aib 
                 α-aminoisobutyric acid 
               
               
                 Ambz(4) 
                 4-aminomethylbenzoyl 
               
               
                 GABA 
                 γ-aminobutyric acid 
               
               
                 Iva 
                 isovaline 
               
               
                 Lys(Ac) 
                 Nε-acetyllysine 
               
               
                 α-MePhe 
                 α-methylphenylalanine 
               
               
                 MeTyr 
                 N-Methyltyrosine 
               
               
                   
               
               
                 Hda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Doda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Trda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Teda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Peda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Heda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Hepda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Oda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Eda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dda 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Pal 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 PEG(2) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (PEG3)2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (PEG3)3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (PEG3)4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (PEG3)5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 PEG(4) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 γGlu 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (γGlu)2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (γGlu)3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (γGlu)2-PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AMBZ-PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GABA- (PEG3)2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GABA-GGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGGGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGGGGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 G9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 NpipAc 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 NpipAc- PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Tra 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Tra-GGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Tra-PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 γGlu-PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 γGlu- (PEG3)2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 γGlu-AMBZ- PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 γGlu-GGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 εLys 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 εLys-GGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 εLys-PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 gE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 OEG = AEEA = PEG3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGGGG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGEEE = G2E3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 G3gEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2OEGgEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 OEGgEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 GGPAPAP 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2OEGgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3OEGgEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 G4gE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 G5gE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2OEGgEgEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2OEG 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 G5gEgE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 gE = γGlu 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C15DA = C 15  diacid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C16DA = C 16  diacid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C17DA = C 17  diacid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C18DA = C 18  diacid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 C20DA = C 20  diacid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ac 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Me-Tyr = MeTyr 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Aib 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
         
             
             
         
       
     
     PEG linkers used for Cys. PEG=5-30 kDA PEG 
     
       
         
         
             
             
         
       
     
     In the specification, where bases, amino acids, etc. are denoted by their codes, they are based on conventional codes in accordance with the IUPAC-IUB Commission on Biochemical Nomenclature or by the common codes in the art, examples of which are shown below. For amino acids that may have an optical isomer, L-form is presented unless otherwise indicated (e.g., “Ala” is L-form of Ala). In addition, “D-” means a D-form (e.g., “D-Ala” is D-form of Ala), and “DL-” means a racemate of a D-form and an L-form (e.g., “DL-Ala” is DL racemate of Ala). 
     The present disclosure is explained in detail in the following by referring to the following Reference Examples, Examples, Test Examples and Formulation Examples, which are mere embodiments and not to be construed as limitative. In addition, the present disclosure may be modified without departing from the scope of invention. 
     The term “room temperature” in the following Examples indicates the range of generally from about 10° C. to about 35° C. As for “%”, the yield is in mol/mol %, the solvent used for chromatography is in % by volume and other “%” is in % by weight. 
     NMP: methylpyrrolidone
 
THF: tetrahydrofuran
 
     DMF: N,N-dimethylformamide 
     WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
     DCC: N,N′-Dicyclohexylcarbodiimide 
     DIPCDI N,N′-diisopropylcarbodiimide
 
HOBt: 1-hydroxybenzotriazole monohydrate
 
Oxyma: ethyl 2-cyano-2-(hydroxyimino)acetate
 
     Example 1. Synthesis Schemes 
     Exemplary methods for synthesizing GIP receptor agonist peptides are disclosed for example in Applicant&#39;s International PCT Application No. PCT/JP2018/013540, filed on Mar. 30, 2018, ranging from pages 162 to 213, the disclosure of which is specifically incorporated herein by reference in its entirety. 
     Example 2. Synthesis of Selective GIP Receptor Agonist Peptides of the Present Disclosure. Compound No. 25; SEQ ID NO: 26 
     The peptide compound 25 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: the 2-CTC Resin (100 g, 50.0 mmol, 1.00 eq, Sub 0.50 mmol/g) was added Fmoc-Gly-OH (14.9 g, 50.0 mmol, 1.00 eq) and DIEA (25.8 g, 200 mmol, 33.1 mL, 4.00 eq) in DCM (250 mL). The mixture was agitated with N 2  for 2 h at 25° C., then added MeOH (100 mL) agitated with N 2  for another 30 min. The resin was washed with DMF (900 mL times 5). Then 20% piperidine in DMF (900 mL) was added and the mixture was agitated with N 2  for 20 min at 25° C. Then the mixture was filtered to get the resin. The resin was washed with DMF (900 mL times 5) and filtered to get the resin. 
     2. Coupling: A solution of Fmoc-Lys(Boc)-OH (70.3 g, 150 mmol, 3.00 eq), DIEA (38.8 g, 300 mmol, 49.7 mL, 6.00 eq) and HBTU (54.1 g, 143 mmol, 2.85 eq) in DMF (250 m 3) was added to the resin and agitated with N 2  for 35 min at 30° C. The resin was then washed with DMF (900 mL times 5). 
     3. Deprotection: 20 piperidine in DMF (900 mL) was added to the resin and the mixture was agitated with N 2  for 20 min at 30′° C. 
     4. Repeat Step 2 and 3 for the coupling of following amino acids: (1-29): 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 FMOC-TRP(BOC)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7 
                 FMOC-VAL-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9 
                 FMOC-LYS(DDE)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11 
                 FMOC-GLN(TRT)-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.0 eq) 
               
               
                 12 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-ARG(PBF)-OH (6.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 15 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ILE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 19 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 20 
                 FMOC-TYR(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 21 
                 FMOC-ASP(OTBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 22 
                 FMOC-SER(TBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 23 
                 FMOC-ILE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 24 
                 FMOC-PHE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 25 
                 FMOC-THR(TBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 26 
                 FMOC-GLY-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 27 
                 FMOC-GLU(OTBU)-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.0 eq) 
               
               
                 28 
                 FMOC-AIB-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 29 
                 FMOC-N-ME-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. Coupling: Boc 2 /DIPEA/DMF (10/5/85) 1400 ma for 30 m, then the resin was washed with DMF (1600 mL times 5). 
     6. Deprotection: Dde was treated with Hydrazine hydrate/DMF (3/97) 1400 mL for 30 min, then the resin was washed with DMF (1600 mL times 5). 
     7. Repeat Step 2 and 3 for the coupling of following amino acids: (1-5): 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 1 
                 Fmoc-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 Fmoc-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 Fmoc-Glu-OtBu (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 Fmoc-Glu-OtBu (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 pentadecanedioic 
                 HOBt (4.00 eq) and DIC (4.00 eq) 
               
               
                   
                 acid (4.00 eq) 
               
               
                   
               
            
           
         
       
     
     Peptide Cleavage and Purification: 
     1. After coupling, the resin was washed with DMF for 5 times. After last step, the resin was washed with MeOH for 3 times and dried under vacuum to get 301 g peptide resin. Then 3000 mL of cleavage buffer (92.5% TFA/2.5% 0  3-Mercaptopropionic acid/2.5% TIS/2.5% H2O) was added to the flask containing the side chain protected peptide resin at 25° C. and the mixture was stirred for 2.5 h. The cleavage buffer was concentrated under reduced pressure to give 1000 mL. The peptide was precipitated with cold tert-butyl methyl ether (7000 mL), then was filtered to give the filter cake, dried the filter cake over vacuum for 2 h to give the crude peptide (182 g) which was confirmed by LCMS (Rt=1.563 min). 
     2. The crude peptide was purified by prep-HPLC (TFA condition; A: 0.075% TFA in H2O, B: CH3CN) to give the peptide, then the peptide was purified by prep-HPLC (HOAC condition; A: 0.5% HOAC in H2O, B: ACN) to give the final product compound 25 (11.86 g, 5.23% yield, 96.23% purity, HOAC) was obtained as a white solid. 
     Purification Conditions: 
     
       
         
           
               
             
               
                   
               
             
            
               
                 First Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.075% TFA in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 21-51-60 min. Retention time: 39 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 50° C. 
               
            
           
           
               
            
               
                 Second Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 The liquid is directly Purification 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.5% HOAc in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min, 
               
               
                   
                 29-49-50 min. Retention time: 61 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 30° C. 
               
               
                   
               
            
           
         
       
     
     Example 3. Synthesis of Selective GIP Receptor Agonist Peptides of the Present Disclosure. Compound No. 142; SEQ ID NO: 143 
     The peptide 142 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: the 2-CTC Resin (100 g, 50.0 mmol, 1.00 eq, Sub 0.50 mmol/g) was added Fmoc-GLY-OH (14.9 g, 50.0 mmol, 1.00 eq) and DIEA (25.85 g, 200.0 mmol, 33.14 mL, 4.00 eq) in DCM (280 mL). The mixture was agitated with N 2  for 2 h at 25° C., then added MeOH (100.0 mL) agitated with N 2  for another 30 min. The resin was washed with DMF (400 mL×5). Then 20% piperidine in DMF (400 mL) was added and the mixture was agitated with N 2  for 15 min at 25° C. Then the mixture was filtered to get the resin. The resin was washed with DMF (400 mL×5) and filtered to get the resin. 
     2. Coupling: a solution of FMOC-ARG(PBF)-OH (97.32 g, 150 mmol, 3.00 eq), HBTU (53.87 g, 142.5 mmol, 2.85 eq) and DIEA (38.772 g, 300 mmol, 49.707 mL, 6.00 eq) in DMF (300 mL) was added to the resin and agitated with N 2  for 40 min at 20° C. The resin was then washed with DMF (400 mL times 3). 
     3. Deprotection: 20% piperidine in DMF (400 mL) was added to the resin and the mixture was agitated with N 2  for 15 min at 20° C. The resin was washed with DMF (400 mL×5) and filtered to get the resin. 
     4. Repeat step 2 to 3 for next amino acid coupling: 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC- LEU -OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 FMOC-TRP(BOC)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7 
                 FMOC-VAL-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 12 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-ARG(PBF)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-ARG(PBF)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 15 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16 
                 FMOC-LYS(DDE)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ILE-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ILE-OH (5.00 eq) 
                 HOAT (5.00 eq) and DIC (5.00 eq) 
               
               
                 19 
                 FMOC-SER(TBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 20 
                 FMOC-TYR(TBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 21 
                 FMOC-ASP(OTBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 22 
                 FMOC-SER(TBU)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 23 
                 FMOC-ILE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 24 
                 FMOC-PHE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 25 
                 FMOC-THR(TBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 26 
                 FMOC-GLY-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 27 
                 FMOC-GLU(OTBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 27 
                 FMOC-GLU(OTBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 28 
                 FMOC-AIB-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 29 
                 FMOC-N-ME-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. Coupling: Boc 2 O/DIPEA/DMF (10/5/85) 500 mL for 30 min and then repeat it for one more time, then the resin was washed with DMF (500 mL×5). 
     6. Deprotection: Dde was treated with Hydrazine hydrate/DMF (3/97) 500 mL for 10 min and then repeat it for one more time, then the resin was washed with DMF (500 mL×5). 
     7. Repeat Step 2 and 3 for all other amino acids: (FMOC-GLY-GLY-GLY-OH, FMOC-GLY-GLY-OH, pentadecanedioic acid). 
     Peptide Cleavage and Purification: 
     1. The resin was washed with MeOH (500 mL×3) and dried under vacuum to get 270 g peptide resin. Then 2800 mL of cleavage buffer (92.5% TFA/2.5% 3-Mercaptopropionic acid/2.5% TIS/2.5% H2O) was added to the flask containing the side chainprotected peptide resin at 20° C. and the mixture was stirred for 2.5 h. The cleavage buffer was concentrated under reduced pressure to give 900 mL. The peptide was precipitated with cold tert-butyl methyl ether (7.20 L), then was filtered to give the filter cake, dried the filter cake over vacuum for 2 h to give the crude peptide (179.5 g) was obtained as a white solid and LCMS. 
     2. The crude peptide was purified by prep-HPLC (TFA condition; A: 0.075% TFA in H2O, B: CH3CN) to give the peptide, then the peptide was purified by prep-HPLC (HOAC condition; A: 0.5% HOAC in H2O, B: ACN) to give the final product. The product (8.39 g) and (3.56 g) was combined for lyophilization to give the final product Compound 142 (11.95 g, 98.49% purity, HOAC) was obtained as a white solid. 
     Purification Conditions: 
     
       
         
           
               
             
               
                   
               
             
            
               
                 First Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.075% TFA in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 24-44-60 min. Retention time: 42 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 50° C. 
               
            
           
           
               
            
               
                 Second Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.5% HOAc in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min, 
               
               
                   
                 30-45-53 min. Retention time: 53 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 50° C. 
               
               
                   
               
            
           
         
       
     
     Example 4. Synthesis of Selective GIP Receptor Agonist Peptides of the Present Disclosure. Compound No. 17; SEQ ID NO: 18 
     The peptide compound 17 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: The Rink Amine MBHA resin (6 mmol, 1.00 eq, 24 g, Sub 0.25 mmol/g) in DMF (250 mL) was agitated with N 2  for 2 hrs at 20° C. Then 20% piperidine in DMF (500 mL) was added and the mixture was agitated with N 2  for 15 mi at 20° C. Then the mixture was filtered to get the resin. The resin was washed with DMF (500 mL times 5) and filtered to get the resin. 
     2. Coupling: a solution of FMOC-SER(TBU)-OH (3.00 eq) and HBTU (2.85 eq), DIEA (6.00 eq) in DMF (250 mL) was added to the resin and agitated with N 2  for 30 min at 20° C. The resin was then washed with DMF (500 mL times 3). 
     3. Deprotection: 20% piperidine in DMF (500 mL) was added to the resin and the mixture was agitated with N 2  for 15 m at 20° C. The resin was washed with DMF (500 mL times 5) and filtered to get the resin. 
     4. Repeat step 2 to 3 for the coupling of following amino acids: (1-38) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-ALA-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 FMOC-GLY-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6 
                 FMOC-SER(TBU)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7 
                 FMOC-SER(TBU)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9 
                 FMOC-SER(TBU)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 12 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-TRP(BOC)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 15 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16 
                 FMOC-VAL-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 19 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 20 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 21 
                 FMOC-LYS(DDE)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 22 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 23 
                 FMOC-ARG(PBF)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 24 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 25 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 26 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 27 
                 FMOC-ILE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 28 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 29 
                 FMOC-TYR(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 30 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 31 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 32 
                 FMOC-ILE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 33 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 34 
                 FMOC-THR(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 35 
                 FMOC-GLY-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 36 
                 FMOC-GLU(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 37 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 38 
                 FMOC-N-ME-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. To a solution of DIEA (5.00 eq) and Boc 2 O (10.00 eq) in DMF (300 mL) was added to the resin and agitated with N 2  for 1 hour at 20° C. Then the resin was washed with DMF (500 mLtimes3). 
     6. Add 3% N 2 H4-H 2 O/DMF and react on 20 mins and then repeat it for one more time. Drain and wash with DMF (500 mLtimes5). 
     7. Repeat step 2 to 3 for the coupling of following amino acids: (1-4) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                 1 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     8. Coupling: a solution of pentadecanedioic acid (2.00 eq) and HOBt (2.00 eq), DIC (2.00 eq) in DMF (250 mL) was added to the resin and agitated with N 2  for 12 hrs at 20° C. The resin was then washed with DMF (500 mLtimes3). 
     9. The coupling reaction was monitored by ninhydrin color reaction. 
     Peptide Cleavage and Purification: 
     1. After coupling, the resin was washed with DMF for 5 times. After last step, the resin was washed with MeOH for 3 times, and dried under vacuum. Then the 50 g peptide resin was treated with the cleavage cocktail (500 mL, 90% TFA/3% 3-Mercaptopropionic acid/3% TIS/4% H2O) for 2.5 hours. The peptide was concentrated under reduced pressure and precipitated with cold isopropyl ether, filtered and washed two times with isopropyl ether to give 22 g residue. 
     2. The crude peptide was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) and then was second purified by Prep-HPLC (A: 0.5% HOAc in H2O, B: ACN) to give the compound 17 (1.23 g, 97.46% purity, HOAC) was obtained as a white solid, which was confirmed by LCMS (Rt=1.563 min) and HPLC. 
     Purification Conditions: 
     
       
         
           
               
             
               
                   
               
             
            
               
                 First Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN-H2O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.075% TFA in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 24-44-60 min. Retention time: 47.5 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 30° C. 
               
            
           
           
               
            
               
                 Second Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.5% HOAc in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min, 
               
               
                   
                 33-48-60 min. Retention time: 57 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 30° C. 
               
               
                   
               
            
           
         
       
     
     Example 5. Synthesis of Selective GIP Receptor Agonist Peptides of the present disclosure. Compound No. 21; SEQ ID NO: 22 
     The peptide compound 21 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: The Rink Amine MBHA resin (0.300 mmol, 1.00 eq, 1.00 g, Sub 0.30 mmol/g) in DMF (5 mL) was agitated with N 2  for 2 hrs at 20° C. Then 20% piperidine in DMF (10 mL) was added and the mixture was agitated with N 2  for 15 min at 20° C. Then the mixture was filtered to get the resin. The resin was washed with DMF (20 mLtimes5) and filtered to get the resin. 
     2. Coupling: a solution of FMOC-SER(TBU)-OH (345 mg, 0.900 mmol, 3.00 eq) and HBTU (323 mg, 0.855 mmol, 2.85 eq), DIEA (233 mg, 1.80 mmol, 6.00 eq) in DMF (50 mL) was added to the resin and agitated with N 2  for 30 min at 20° C. The resin was then washed with DMF (20 mLtimes5). 
     3. Deprotection: 20% piperidine in DMF (20 mL) was added to the resin and the mixture was agitated with N 2  for 15 min at 20° C. The resin was washed with DMF (20 mLtimes5) and filtered to get the resin. 
     4. Repeat step 2 to 3 for the coupling of following amino acids: (1-38) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-ALA-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 FMOC-GLY-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6 
                 FMOC-SER(TBU)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7 
                 FMOC-SER(TBU)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8 
                 FMOC-PRO-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9 
                 FMOC-LYS(DDE)-OH(3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 12 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-TRP(BOC)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 15 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16 
                 FMOC-VAL-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 19 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 20 
                 FMOC-GLN(TRT)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 21 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 22 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 23 
                 FMOC-ARG(PBF)-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.00 eq) 
               
               
                 24 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 25 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 26 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 27 
                 FMOC-ILE-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.00 eq) 
               
               
                 28 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 29 
                 FMOC-TYR(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 30 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 31 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 32 
                 FMOC-ILE-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 33 
                 FMOC-PHE-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 34 
                 FMOC-THR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 35 
                 FMOC-GLY-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 36 
                 FMOC-GLU(OTBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 37 
                 FMOC-AIB-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 38 
                 FMOC-N-ME-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. Coupling: Boc 2 O/DIPEA/DMF (10/5/85) 20 mL for 15 mintimes 2, then the resin was washed with DMF (20 mL times 5). 
     6. Add 3% N 2 H 4 .H 2 O/DMF and react on 20 mins and then repeat it for one more time. Drain and wash with DMF (20 mLtimes5). 
     7. Repeat step 2 to 3 for the coupling of following amino acids: 01-4) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                 1 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     8. Coupling: a solution of pentadecanedioic acid (3.00 eq) and HOBt (3.00 eq), DIC (3.00 eq) in DMF (10 mL) was added to the resin and agitated with N 2  for 12 hrs at 20° C. The resin was then washed with DMF (20 mLtimes3). 
     9. The coupling reaction was monitored by ninhydrin color reaction. 
     Peptide Cleavage and Purification: 
     1. After coupling, the resin was washed with DMF for 5 times. After last step, the resin was washed with MeOH for 3 times, and dried under vacuum to get 1.5 g peptide resin. Then the peptide resin was treated with the cleavage cocktail (15 mL, 92.5% TFA/2.5% 3-Mercaptopropionic acid/2.5% TIS/2.5% H 2 O) for 2.5 hours. The peptide was concentrated under reduced pressure and precipitated with cold isopropyl ether, filtered and washed two times with isopropyl ether to give 1.2 g residue. 
     2. The crude peptide was purified by Prep-HPLC (A: 0.075% TFA in H 2 O, B: ACN) and then was second purified by Prep-HPLC (A: 0.5% HOAc in H 2 O, B: ACN) to give the compound 21 (60.6 mg, 99.13% purity, HOAC) as a white solid which was confirmed by LCMS (Rt=1.533 min) and HPLC (Rt=11.392 min). 
     Purification Conditions: 
     
       
         
           
               
             
               
                   
               
             
            
               
                 First Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 10% ACN-H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.075% TFA in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 27-47-60 min. Retention time: 42 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 30° C. 
               
            
           
           
               
            
               
                 Second Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 10% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.5% HOAc in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min, 
               
               
                   
                 30-45-60 min. Retention time: 65 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 30° C. 
               
               
                   
               
            
           
         
       
     
     Example 6. Synthesis of Selective GIP Receptor Agonist Peptides of the Present Disclosure. Compound No. 48; SEQ ID NO: 43 
     The peptide compound 48 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: the 2-CTC Resin (800 mg, 0.400 mmol, 1.00 eq, Sub 0.50 mmol/g) was added Fmoc-Ser(tBu)-OH (153 mg, 0.400 mmol, 1.00 eq) and DIEA (207 mg, 1.60 mmol, 0.279 mL, 4.00 eq) in DCM (5.00 mL). The mixture was agitated with N 2  for 2 h at 25° C., then added MeOH (0.800 mL) agitated with N 2  for another 30 min. The resin was washed with DMF (30.0 mL times 5). Then 20% piperidine in DMF (30.0 mL) was added and the mixture was agitated with N 2  for 15 min at 25° C. Then the mixture was filtered to get the resin. The resin was washed with DMF (30.0 mL times 5) and filtered to get the resin. 
     2. Coupling: A solution of Fmoc-Pro-OH (405 mg 1.20 mmol, 3.00 eq), DIEA (310 mg, 2.40 mmol, 0.418 mL, 6.00 eq) and HBTU (432 mg, 1.14 mmol, 2.85 eq) in DMF (5.00 mL) was added to the resin and agitated with N 2  for 30 min at 25° C. The resin was then washed with DMF (30.0 mL times 5). 
     3. Deprotection: 20% piperidine in DMF (30.0 mL) was added to the resin and the mixture was agitated with N 2  for 15 min at 25° C. 
     4. Repeat Step 2 and 3 for the coupling of following amino acids: (1-37): 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1. 
                 Fmoc-Pro-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2. 
                 Fmoc-Pro-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3. 
                 Fmoc-Ala-OH(3.0 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4. 
                 Fmoc-Gly-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5. 
                 Fmoc-Ser(tBu)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6. 
                 Fmoc-Ser(tBu)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7. 
                 Fmoc-Pro-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8. 
                 Fmoc-Ser(tBu)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9. 
                 Fmoc-Gln(Trt)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10. 
                 Fmoc-Ala-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11. 
                 Fmoc-Leu-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 12. 
                 Fmoc-Leu-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13. 
                 Fmoc-Trp(Boc)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14. 
                 Fmoc-Asn(Trt)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 15. 
                 Fmoc-Val-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16. 
                 Fmoc-Phe-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17. 
                 Fmoc-Asn(Trt)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18. 
                 Fmoc-Aib-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 19. 
                 Fmoc-Gln(Trt)-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.0 eq) 
               
               
                 20. 
                 Fmoc-Ala-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 21. 
                 Fmoc-Aib-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 22. 
                 Fmoc-Arg(pbf)-OH (6.00 eq) 
                 HATU (5.70 eq) and DIEA (12.0 eq) 
               
               
                 23. 
                 Fmoc-Asp(OtBu)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 24. 
                 Fmoc-Lys(Dde)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 25. 
                 Fmoc-Ala-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 26. 
                 Fmoc-Ile-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 27. 
                 Fmoc-Ser(tBu)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 28. 
                 Fmoc-Tyr(tBu)-OH (4.00 eq) 
                 HBTU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 29. 
                 Fmoc-Asp(OtBu)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 30. 
                 Fmoc-Ser(tBu)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 31. 
                 Fmoc-Ile-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 32. 
                 Fmoc-Phe-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 33. 
                 Fmoc-Thr(tBu)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 34. 
                 Fmoc-Gly-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 35. 
                 Fmoc-Glu(OtBu)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 36. 
                 Fmoc-Aib-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 37. 
                 Fmoc-N-Me-Tyr(tBu)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. Coupling: Boc 2 O/DIPEA/DMF (10/5/85) 50.0 mL for 30 min, then the resin was washed with DMF (30.0 mL times 5). 
     6. Deprotection: Dde was treated with Hydrazine hydrate/DMF (3/97) 50.0 mL for 30 min, then the resin was washed with DMF (30.0 mL times 5). 
     Repeat Step 2 and 3 for the coupling of following amino acids: (1-3): 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 1 
                 Fmoc-Gly-Gly-Gly-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 Fmoc-Gly-Gly-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 pentadecanedioic 
                 HOBt (4.00 eq) and DIC (4.00 eq) 
               
               
                   
                 acid (4.00 eq) 
               
               
                   
               
            
           
         
       
     
     Peptide Cleavage and Purification: 
     1. The resin was washed with MeOH (30 mLtimes3) and dried under vacuum to get 3.00 g peptide resin. Then 30.0 mL of cleavage buffer (92.5% TFA/2.5% 0  3-Mercaptopropionic acid/2.5% TIS/2.5% H2O) was added to the flask containing the side chain protected peptide resin at 25° C. and the mixture was stirred for 2.5 h. The peptide was precipitated with cold isopropyl ether (200 mL) and centrifuged (3 min at 3000 rpm). Wash the peptide precipitation with tert-butyl methyl ether for two more times (200 mL). Dry the crude peptide over vacuum for 2 h to give the crude peptide (1.70 g). 
     2. The crude peptide was purified by prep-HPLC (TFA condition; A: 0.075% TFA in H 2 O, B: CH 3 CN) to give the peptide, then the peptide was purified by prep-HPLC (HOAC condition; A: 0.5% HOAC in H 2 O, B: ACN) to give the final product compound 48 (152.7 mg, 8.08% yield, 97.1% purity, HOAC) was obtained as a white solid. 
     Purification Conditions: 
     
       
         
           
               
             
               
                   
               
             
            
               
                 First Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.075% TFA in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 25-45-60 min. Retention time: 42.5 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 50° C. 
               
            
           
           
               
            
               
                 Second Purification condition 
               
            
           
           
               
               
            
               
                 Dissolution 
                 Dissolve in 20% ACN in H 2 O 
               
               
                 condition 
               
               
                 Instrument 
                 Gilson GX-281 
               
               
                 Mobile Phase 
                 A: H 2 O (0.5% HOAc in H 2 O) 
               
               
                   
                 B: ACN 
               
               
                 Gradient 
                 0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min, 
               
               
                   
                 25-40-50 min. Retention time: 68 min 
               
               
                 Column 
                 luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A 
               
               
                 Flow Rate 
                 20 mL/Min 
               
               
                 Wavelength 
                 214/254 nm 
               
               
                 Oven Tem. 
                 50° C. 
               
               
                   
               
            
           
         
       
     
     Example 7. Synthesis of Selective GIP Receptor Agonist Peptides of the Present Disclosure. Compound No. 14; SEQ ID NO: 15 
     The peptide compound 14 was synthesized using standard Fmoc chemistry. 
     1. Resin preparation: To the Rink Amide MBHA resin (0.300 mmol, 1.00 eq, Sub 0.280 mmol/g) in DMF (5.00 mL) was agitated with N 2  for 2 heat 20° C. Then 20% piperidine in DMF (20.0 mL) was added and the mixture was agitated with N 2  for 30 min at 20° C. The resin was washed with DMF (20.0 mL times 5) and filtered to get the resin. 
     2. Coupling: A solution of FMOC-ARG(PBF)-OH (584 mg, 900 umol, 3.00 eq), DIEA (232 mg, 1.80 mmol, 314 uL, 6.00 eq) and HBTU (324 mg, 855 umol, 2.85 eq) in DMF (2.00 mL) was added to the resin and agitated with N 2  for 30 min at 20° C. The resin was then washed with DMF (20.0 mL times 3). 
     3. Deprotection: 200 piperidine in DMF (20.0 mL) was added to the resin and the mixture was agitated with N 2  for 30 min at 20° C. The resin was washed with DMF (20.0 mL times 5) and filtered to get the resin. 
     4. Repeat step 2 to 3 for the coupling of following amino acids: (1-29): 
     
       
         
           
               
               
               
             
               
                   
               
               
                 # 
                 Materials 
                 Coupling reagents 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 FMOC-GLN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC- LEU -OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 FMOC-TRP(BOC)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 6 
                 FMOC-ASN(TRT)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 7 
                 FMOC-VAL-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 8 
                 FMOC-PHE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 9 
                 FMOC-LYS(DDE)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 10 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 11 
                 FMOC-GLN(TRT)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 12 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 13 
                 FMOC-AIB-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 14 
                 FMOC-ARG(PBF)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 15 
                 FMOC-ASP(OTBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 16 
                 FMOC-LEU-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 17 
                 FMOC-ALA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 18 
                 FMOC-ILE-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 19 
                 FMOC-SER(TBU)-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 20 
                 FMOC-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 21 
                 FMOC-ASP(OTBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 22 
                 FMOC-SER(TBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 23 
                 FMOC-ILE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 24 
                 FMOC-PHE-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 25 
                 FMOC-THR(TBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 26 
                 FMOC-GLY-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 27 
                 FMOC-GLU(OTBU)-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 28 
                 FMOC-AIB-OH (4.00 eq) 
                 HATU (3.80 eq) and DIEA (8.00 eq) 
               
               
                 29 
                 FMOC-N-ME-TYR(TBU)-OH (3.00 eq) 
                 HATU (2.85 eq) and DIEA (6.00 eq) 
               
               
                   
               
            
           
         
       
     
     5. Coupling: Boc 2 O/DIPEA/DMF (10/5/85) 20.0 mL for 30 min, then the resin was washed with DMF (20.0 mL times 5). 
     6. Deprotection: Dde was treated with Hydrazine hydrate/DMF (3/97) 20.0 mL for 30 min, then the resin was washed with DMF (30.0 mL times 5). 
     7. Repeat step 2 to 3 for the coupling of following amino acids: (1-5): 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 1 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 2 
                 FMOC-AEEA-OH (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 3 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 4 
                 FMOC-GLU-OTBU (3.00 eq) 
                 HBTU (2.85 eq) and DIEA (6.00 eq) 
               
               
                 5 
                 pentadecanedioic 
                 HOBT (4.00 eq) and DIC (4.00 eq) 
               
               
                   
                 acid (4.00 eq) 
               
               
                   
               
            
           
         
       
     
     Peptide Cleavage and Purification: 
     1. The resin was washed with MeOH (30 mLtimes2) and dried under vacuum to get 3.5 g peptide resin. Then 30 mL of cleavage buffer (92.5% TFA/2.5% 0  3-Mercaptopropionic acid/2.5% TIS/2.5% H2O) was added to the flask containing the side chainprotected peptide resin at 20° C. and the mixture was stirred for 2 h. The peptide was precipitated with cold tert-butyl methylether (250 mL) and centrifuged (3 min at 3000 rpm). Wash the peptide precipitation with tert-butyl methyl ether for two more times (120 mL). Dry the crude peptide (1.4 g) over vacuum for 2 h. 
     2. The residue was purified by prep-HPLC (TFA condition; 30° C., A: 0.07500 TFA/1H2O, B: CH3CN) and then was second purified by prep-HPLC (HOAc condition; 30° C., A: 0.5% HOAc/H2O, B: CH3CN) to give the product to give the compound 14 (79.8 mg, 6.22% yield, 96.4% purity, HOAC) as a white solid. 
     Purification Conditions: 
                                First Purification condition                     Dissolution   Dissolve in 20% TFA, 10% CH 3 CN and 70% H 2 O       condition       Instrument   Gilson GX-281       Mobile Phase   A: H 2 O (0.075% TFA in H 2 O)           B: ACN       Gradient   24-44-60 min. Retention time: 43 min       Column   luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A       Flow Rate   20 mL/Min       Wavelength   214/254 nm       Oven Tem.   20° C.                 Second Purification condition                     Dissolution   The liquid is directly Purification       condition       Instrument   Gilson GX-281       Mobile Phase   A: H 2 O (0.5% HOAc in H 2 O)           B: ACN       Gradient   0.4M NH 4 Ac 25 min, 0.5% HOAc 10 min,           28-38-60 min. Retention time: 52 min       Column   luna, c18, 10 um, 100 A + Gemini, 5 um, c18, 110 A       Flow Rate   20 mL/Min       Wavelength   214/254 nm       Oven Tem.   Room temperature                    
Table 3 below lists exemplary GIP receptor agonist peptides made according to methods described in Example 1-7.
 
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Exemplary GIP receptor agonist peptides made according to methods described in Examples 1-7 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 CPMD No. 
                 LINKER 
                 LIPID 
                 N_TER 
                 C_TER 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
               
               
                   
               
               
                 1 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 2 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 3 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 4 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 5 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 6 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 S 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 7 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 8 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 9 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 10 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 11 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 12 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 13 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 14 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 15 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 16 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 17 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 18 
                 gEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 19 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 20 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 21 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 22 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 23 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 24 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 25 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 26 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 27 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 28 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 29 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 30 
                 G2E3 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 31 
                 G2E3 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 32 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 33 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 34 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 35 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 36 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 37 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 38 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 39 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 40 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 41 
                 G2E3 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 42 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 43 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 44 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 45 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 46 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 47 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 48 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 49 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 50 
                    E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 51 
                    E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 52 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 53 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 54 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 55 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 56 
                 
                   
                 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 57 
                 
                   
                 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 58 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 59 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 60 
                    gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 61 
                    E 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 62 
                    gE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 63 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 64 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 65 
                    gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 66 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 67 
                    gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 68 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 69 
                    gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 70 
                 OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 71 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 72 
                    gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 73 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 74 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 75 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 76 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 77 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 78 
                 G4gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 79 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 80 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 81 
                 G5gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 82 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 83 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 84 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 85 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 86 
                 OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 87 
                    GgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 88 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 89 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 90 
                    gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 91 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 92 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 93 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 94 
                 OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 95 
                 GGEEE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 96 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 97 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 98 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 99 
                 GGEEE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 100 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 101 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 102 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 103 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 104 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 105 
                 GGEEE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 106 
                    PAPAP 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 107 
                    PAPAP 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 108 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 109 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 110 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 111 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 112 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 113 
                 GG-EEE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 114 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 115 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 116 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 117 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 118 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 119 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 120 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 121 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 122 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 123 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 124 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 125 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 126 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 127 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 128 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 129 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 130 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 131 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 132 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 133 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 134 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 135 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 136 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 137 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 138 
                 G2E3 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 139 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 140 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 141 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 142 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 143 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 144 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 145 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 146 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 147 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 148 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 149 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 150 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 151 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 152 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 153 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 154 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 155 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 156 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 157 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 158 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 159 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 160 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 161 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 162 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 163 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 164 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 165 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 166 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 167 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 168 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 169 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 170 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 171 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 172 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 173 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 174 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 175 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 176 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 177 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 178 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 179 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 180 
                 G4gE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 181 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 182 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 183 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 184 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 185 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 186 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 187 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 188 
                 2OEGgEgE 
                 C15DA 
                   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 189 
                 GS 
                 C15DA 
                   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 190 
                 gE 
                 C16 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 191 
                   
                 C16 
                   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 192 
                 2OEGgE 
                 C16DA 
                   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 193 
                 PEG  gE 
                 C16DA 
                   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 194 
                 PEG  gE 
                 C16DA 
                   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 195 
                 PEG  gE 
                 C16DA 
                   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 196 
                 2OEGgE 
                 C16DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 197 
                 gEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 198 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 199 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 200 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 201 
                 2OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 202 
                 2OEGgEgE 
                 C16 (  ) 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 203 
                 2OEGgEgE 
                 C16 (  ) 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 204 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 205 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 206 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 207 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 208 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 209 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 210 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 211 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 212 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 213 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 214 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 215 
                 GSgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 216 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 
                   
                 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 217 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 A 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 218 
                 2OEG 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 219 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 220 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 221 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 222 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 223 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 224 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 225 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 226 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 227 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 228 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 229 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 230 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 231 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 232 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 233 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 234 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 235 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 236 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 237 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 238 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 239 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 240 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 241 
                 2OEGgE 
                 C15DA 
                   
                   
                 Y 
                 A 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 242 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 243 
                 2OEGgE 
                 C15DA 
                 M   
                   
                 Y 
                 G 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 244 
                 2OEGgE 
                 C15DA 
                   
                   
                 Y 
                 S 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 245 
                 2OEGgE 
                 C15DA 
                   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 246 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 247 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 248 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 249 
                 G2E3 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 250 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 251 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 252 
                    PAPAP 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 253 
                 2OEGgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 254 
                 OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 255 
                 GGPAPAP 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 256 
                 GGPAPAP 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 257 
                 G3gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 258 
                 G3gEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 259 
                 G5gE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 260 
                 G5gEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 261 
                 G3E2 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 262 
                 G3E2 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 L 
                 Y 
                 S 
                 I 
               
               
                 263 
                 GSgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 264 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 265 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 266 
                 2OEGgEgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 267 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 268 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 L 
                 Y 
                 S 
                 I 
               
               
                 269 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 270 
                 GSgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 271 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 272 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 273 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 274 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 275 
                 GSgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 276 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 277 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 278 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 279 
                 GSgE 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 280 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 281 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 282 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 283 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 284 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 285 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 286 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 287 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 288 
                 GSgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 289 
                 OEGgEgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 290 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 291 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 292 
                 2OEG 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 293 
                 2OEGgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 294 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 295 
                 2OEGgEgE 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 296 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 297 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 298 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 299 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 300 
                 GS 
                 C15DA 
                 M   
                 NH2 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 301 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 302 
                 GS 
                 C15DA 
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 303 
                 gE 
                 C16 
                   
                   
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 304 
                 Ac 
                   
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                 305 
                 Ac 
                   
                 M   
                 OH 
                 Y 
                 Aib 
                 E 
                 G 
                 T 
                 F 
                 I 
                 S 
                 D 
                 Y 
                 S 
                 I 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 CPMD No. 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
               
               
                   
               
               
                 1 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 2 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 3 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 4 
                 A 
                 L 
                 D 
                 R 
                   
                 H 
                 Q 
                 Km 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 5 
                 A 
                 L 
                 D 
                 R 
                   
                 H 
                 Q 
                 Km 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 6 
                 A 
                 Km 
                 D 
                 R 
                   
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 7 
                 A 
                 Km 
                 D 
                 R 
                   
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 8 
                 A 
                 L 
                 D 
                 R 
                   
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 9 
                 A 
                 L 
                 D 
                 R 
                   
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 10 
                 A 
                 L 
                 D 
                 R 
                   
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 Km 
               
               
                 11 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 12 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 13 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 14 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 15 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 16 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 17 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 18 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 19 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 20 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 21 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 22 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 23 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 24 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 25 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 26 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 27 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 28 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 Aib 
               
               
                 29 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 Aib 
               
               
                 30 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 31 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 32 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 33 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 34 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 35 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 36 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 O 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 37 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 38 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 Aib 
               
               
                 39 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 40 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 Aib 
               
               
                 41 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 42 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 43 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 44 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 45 
                 Y 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 46 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 47 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 48 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 49 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 50 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 51 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 52 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 53 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 54 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 55 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 56 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 57 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 58 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 59 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 60 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 61 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 62 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 63 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 64 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 65 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 66 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 67 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 68 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 69 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 70 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 71 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 72 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 73 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 74 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 75 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 76 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 77 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 78 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 79 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 80 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 81 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 82 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 83 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 84 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 85 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 86 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 87 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 88 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 89 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 90 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 91 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 92 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 93 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 94 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 95 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 96 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 97 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 98 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 99 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 100 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 101 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 102 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 103 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 104 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 105 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 106 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 107 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 108 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 109 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 110 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 111 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 112 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 113 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 114 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 115 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 116 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 117 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 118 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 119 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 120 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 121 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 122 
                 Aib 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 123 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 124 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 125 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 126 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 127 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 128 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 129 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 130 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 131 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 132 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 133 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 134 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 135 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 136 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 137 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 138 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 139 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 140 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 141 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 142 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 143 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 144 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 145 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 146 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 147 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 148 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 149 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 150 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 151 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 152 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 153 
                 A 
                 Km 
                 D 
                 S 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 154 
                 A 
                 Km 
                 D 
                 S 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 155 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 156 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 157 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 158 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 159 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 160 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 161 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 162 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 163 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 164 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 165 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 166 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 167 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 168 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 169 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 170 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 171 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 172 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 173 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 174 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 175 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 176 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 177 
                 A 
                 Km 
                 D 
                 S 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 178 
                 Aib 
                 L 
                 D 
                 S 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 179 
                 A 
                 L 
                 D 
                 S 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 180 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 181 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 182 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 183 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 184 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 185 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 186 
                 Aib 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 187 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 188 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 189 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 190 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 Km 
                 L 
                 A 
               
               
                 191 
                 V 
                 L 
                 D 
                 R 
                 Q 
                 A 
                 A 
                 Aib 
                 E 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 192 
                 A 
                 Km 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 193 
                 A 
                 Km 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 194 
                 A 
                 Km 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 195 
                 A 
                 Km 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 196 
                 A 
                 Km 
                 D 
                 R 
                 I 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 197 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 198 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 199 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 200 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 201 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 202 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 203 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 204 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 205 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 206 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 207 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 208 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 209 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 210 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 211 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 212 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 213 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 214 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 215 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 216 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 217 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 218 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 219 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 220 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 221 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 222 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 223 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 224 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 225 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Km 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 226 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 227 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 228 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 229 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 230 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 231 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 232 
                 A 
                 L 
                 D 
                 R 
                 I 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 233 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 234 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 235 
                 A 
                 L 
                 D 
                 R 
                 I 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 236 
                 A 
                 L 
                 D 
                 R 
                 I 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 237 
                 A 
                 L 
                 D 
                 R 
                 I 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 238 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 239 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 240 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Q 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 241 
                 A 
                 L 
                 D 
                 R 
                 I 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 242 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 243 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 244 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 245 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 246 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 247 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 248 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 249 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 250 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 251 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 252 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 253 
                 A 
                 L 
                 D 
                 K 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 254 
                 A 
                 L 
                 D 
                 K 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 255 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 256 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 257 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 258 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 259 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 260 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 261 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 262 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 263 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 264 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 265 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 266 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 267 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 268 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 269 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 270 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 271 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 272 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 273 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 274 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 275 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 276 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 277 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 278 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 H 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 279 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 280 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 281 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 282 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 283 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 284 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 285 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 286 
                 Aib 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 287 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 288 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 289 
                 Aib 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 290 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 Km 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 291 
                 Aib 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 292 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 293 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 294 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 295 
                 Aib 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 296 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 N 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 297 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 298 
                 A 
                 Km 
                 D 
                 S 
                 Aib 
                 A 
                 Q 
                 Aib 
                 
                   
                 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 299 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 300 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 301 
                 A 
                 L 
                 D 
                 R 
                 Km 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 302 
                 A 
                 Km 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 303 
                 A 
                 M 
                 D 
                 K 
                 Km 
                 H 
                 Q 
                 Q 
                 D 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 304 
                 A 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                 305 
                 Aib 
                 L 
                 D 
                 R 
                 Aib 
                 A 
                 Q 
                 Aib 
                 Km 
                 F 
                 V 
                 N 
                 W 
                 L 
                 L 
                 A 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 SEQ 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ID 
               
               
                   
                 CPMD No. 
                 29 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 NO. 
               
               
                   
                   
               
               
                   
                 1 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
               
               
                   
                 2 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
               
               
                   
                 3 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 4 
               
               
                   
                 4 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 5 
               
               
                   
                 5 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 6 
               
               
                   
                 6 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 7 
               
               
                   
                 7 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 8 
               
               
                   
                 8 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 9 
               
               
                   
                 9 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 10 
               
               
                   
                 10 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 11 
               
               
                   
                 11 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 12 
               
               
                   
                 12 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 13 
               
               
                   
                 13 
                 Q 
                 R 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 14 
               
               
                   
                 14 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 15 
               
               
                   
                 15 
                 Q 
                 R 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 16 
               
               
                   
                 16 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 17 
               
               
                   
                 17 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 18 
               
               
                   
                 18 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 19 
               
               
                   
                 19 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 20 
               
               
                   
                 20 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 21 
               
               
                   
                 21 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 22 
               
               
                   
                 22 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 23 
               
               
                   
                 23 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 24 
               
               
                   
                 24 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 25 
               
               
                   
                 25 
                 Q 
                 K 
                 O 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 26 
               
               
                   
                 26 
                 Q 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 27 
               
               
                   
                 27 
                 Q 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 28 
               
               
                   
                 28 
                 Q 
                 E 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 29 
               
               
                   
                 29 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 30 
               
               
                   
                 30 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 31 
               
               
                   
                 31 
                 Q 
                 E 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 32 
               
               
                   
                 32 
                 Q 
                 Km 
                 P 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 33 
               
               
                   
                 33 
                 Q 
                 
                   
                 
                 P 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 34 
               
               
                   
                 34 
                 Km 
                 
                   
                 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 35 
               
               
                   
                 35 
                 Km 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 36 
               
               
                   
                 36 
                 Km 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 37 
               
               
                   
                 37 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 38 
               
               
                   
                 38 
                 Q 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 39 
               
               
                   
                 39 
                 Aib 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 40 
               
               
                   
                 40 
                 Q 
                 
                   
                 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 41 
               
               
                   
                 41 
                 Q 
                 Km 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 42 
               
               
                   
                 42 
                 Q 
                 K 
                 
                   
                 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 43 
               
               
                   
                 43 
                 Q 
                 Km 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 44 
               
               
                   
                 44 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 45 
               
               
                   
                 45 
                 Aib 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 46 
               
               
                   
                 46 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 47 
               
               
                   
                 47 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 48 
               
               
                   
                 48 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 49 
               
               
                   
                 49 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 50 
               
               
                   
                 50 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 51 
               
               
                   
                 51 
                 Q 
                 
                   
                 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 52 
               
               
                   
                 52 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 53 
               
               
                   
                 53 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 54 
               
               
                   
                 54 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 55 
               
               
                   
                 55 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 56 
               
               
                   
                 56 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 57 
               
               
                   
                 57 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 58 
               
               
                   
                 58 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 59 
               
               
                   
                 59 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 60 
               
               
                   
                 60 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 61 
               
               
                   
                 61 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 62 
               
               
                   
                 62 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 63 
               
               
                   
                 63 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 64 
               
               
                   
                 64 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 65 
               
               
                   
                 65 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 66 
               
               
                   
                 66 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 67 
               
               
                   
                 67 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 68 
               
               
                   
                 68 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 69 
               
               
                   
                 69 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 70 
               
               
                   
                 70 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 71 
               
               
                   
                 71 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 72 
               
               
                   
                 72 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 73 
               
               
                   
                 73 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 74 
               
               
                   
                 74 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 75 
               
               
                   
                 75 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 76 
               
               
                   
                 76 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 77 
               
               
                   
                 77 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 78 
               
               
                   
                 78 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 79 
               
               
                   
                 79 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 80 
               
               
                   
                 80 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 81 
               
               
                   
                 81 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 82 
               
               
                   
                 82 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 83 
               
               
                   
                 83 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 84 
               
               
                   
                 84 
                 Km 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 85 
               
               
                   
                 85 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 86 
               
               
                   
                 86 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 87 
               
               
                   
                 87 
                 Km 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 88 
               
               
                   
                 88 
                 Km 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 89 
               
               
                   
                 89 
                 Q 
                 Km 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 90 
               
               
                   
                 90 
                 Q 
                 Km 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 91 
               
               
                   
                 91 
                 Q 
                 Km 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 92 
               
               
                   
                 92 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 93 
               
               
                   
                 93 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 94 
               
               
                   
                 94 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 95 
               
               
                   
                 95 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 96 
               
               
                   
                 96 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 97 
               
               
                   
                 97 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 98 
               
               
                   
                 98 
                 Km 
                 S 
                 P 
                 S 
                 S 
                 G 
                 NH2 
                   
                   
                   
                   
                   
                 99 
               
               
                   
                 99 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 100 
               
               
                   
                 100 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 101 
               
               
                   
                 101 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 102 
               
               
                   
                 102 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 103 
               
               
                   
                 103 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 104 
               
               
                   
                 104 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 105 
               
               
                   
                 105 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 106 
               
               
                   
                 106 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 107 
               
               
                   
                 107 
                 Km 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 108 
               
               
                   
                 108 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 109 
               
               
                   
                 109 
                 Km 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 110 
               
               
                   
                 110 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                 P 
                 P 
                 S 
                 NH2 
                 111 
               
               
                   
                 111 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 112 
               
               
                   
                 112 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 113 
               
               
                   
                 113 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 114 
               
               
                   
                 114 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 115 
               
               
                   
                 115 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 116 
               
               
                   
                 116 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 117 
               
               
                   
                 117 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 118 
               
               
                   
                 118 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 119 
               
               
                   
                 119 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 120 
               
               
                   
                 120 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 121 
               
               
                   
                 121 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 122 
               
               
                   
                 122 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 123 
               
               
                   
                 123 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 124 
               
               
                   
                 124 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 E 
                 P 
                 K 
                 K 
                 K 
                 NH2 
                 125 
               
               
                   
                 125 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 126 
               
               
                   
                 126 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 127 
               
               
                   
                 127 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 128 
               
               
                   
                 128 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 129 
               
               
                   
                 129 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 130 
               
               
                   
                 130 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 131 
               
               
                   
                 131 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 132 
               
               
                   
                 132 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 133 
               
               
                   
                 133 
                 Q 
                 S 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 134 
               
               
                   
                 134 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 135 
               
               
                   
                 135 
                 Q 
                 R 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 136 
               
               
                   
                 136 
                 Q 
                 Km 
                 G 
                 G 
                 G 
                 G 
                 S 
                 NH2 
                   
                   
                   
                   
                 137 
               
               
                   
                 137 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 138 
               
               
                   
                 138 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 139 
               
               
                   
                 139 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 140 
               
               
                   
                 140 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 141 
               
               
                   
                 141 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 142 
               
               
                   
                 142 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 143 
               
               
                   
                 143 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 144 
               
               
                   
                 144 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 145 
               
               
                   
                 145 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 146 
               
               
                   
                 146 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 147 
               
               
                   
                 147 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 148 
               
               
                   
                 148 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 149 
               
               
                   
                 149 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 150 
               
               
                   
                 150 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 151 
               
               
                   
                 151 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 152 
               
               
                   
                 152 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 G 
                 OH 
                 153 
               
               
                   
                 153 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 154 
               
               
                   
                 154 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 155 
               
               
                   
                 155 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 156 
               
               
                   
                 156 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 157 
               
               
                   
                 157 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 G 
                 OH 
                   
                   
                 158 
               
               
                   
                 158 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                 159 
               
               
                   
                 159 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 160 
               
               
                   
                 160 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 161 
               
               
                   
                 161 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 162 
               
               
                   
                 162 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 163 
               
               
                   
                 163 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 164 
               
               
                   
                 164 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 165 
               
               
                   
                 165 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 166 
               
               
                   
                 166 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 167 
               
               
                   
                 167 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 168 
               
               
                   
                 168 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 169 
               
               
                   
                 169 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 170 
               
               
                   
                 170 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 171 
               
               
                   
                 171 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 172 
               
               
                   
                 172 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 173 
               
               
                   
                 173 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 174 
               
               
                   
                 174 
                 Q 
                 S 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 175 
               
               
                   
                 175 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 176 
               
               
                   
                 176 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 177 
               
               
                   
                 177 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 178 
               
               
                   
                 178 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 179 
               
               
                   
                 179 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 180 
               
               
                   
                 180 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 181 
               
               
                   
                 181 
                 Q 
                 K(Ac) 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 182 
               
               
                   
                 182 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 183 
               
               
                   
                 183 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 184 
               
               
                   
                 184 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 185 
               
               
                   
                 185 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 186 
               
               
                   
                 186 
                 Q 
                 S 
                 P 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                 187 
               
               
                   
                 187 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 188 
               
               
                   
                 188 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 189 
               
               
                   
                 189 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 190 
               
               
                   
                 190 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 191 
               
               
                   
                 191 
                 G 
                 G 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 Km 
                 192 
               
               
                   
                 192 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 193 
               
               
                   
                 193 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 194 
               
               
                   
                 194 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 195 
               
               
                   
                 195 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 196 
               
               
                   
                 196 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 197 
               
               
                   
                 197 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 198 
               
               
                   
                 198 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 199 
               
               
                   
                 199 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 200 
               
               
                   
                 200 
                 Q 
                 K 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 201 
               
               
                   
                 201 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 202 
               
               
                   
                 202 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 203 
               
               
                   
                 203 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 204 
               
               
                   
                 204 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 205 
               
               
                   
                 205 
                 Q 
                 K 
                 G 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                 206 
               
               
                   
                 206 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 207 
               
               
                   
                 207 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 208 
               
               
                   
                 208 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 209 
               
               
                   
                 209 
                 Q 
                 K 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 210 
               
               
                   
                 210 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 211 
               
               
                   
                 211 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 212 
               
               
                   
                 212 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 213 
               
               
                   
                 213 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 214 
               
               
                   
                 214 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 215 
               
               
                   
                 215 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 216 
               
               
                   
                 216 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 217 
               
               
                   
                 217 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 218 
               
               
                   
                 218 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 219 
               
               
                   
                 219 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 220 
               
               
                   
                 220 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 221 
               
               
                   
                 221 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 222 
               
               
                   
                 222 
                 Km 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 223 
               
               
                   
                 223 
                 Q 
                 Km 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 224 
               
               
                   
                 224 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 225 
               
               
                   
                 225 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 226 
               
               
                   
                 226 
                 Q 
                 Km 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 227 
               
               
                   
                 227 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 228 
               
               
                   
                 228 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 229 
               
               
                   
                 229 
                 Q 
                 Km 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 230 
               
               
                   
                 230 
                 Q 
                 Km 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 231 
               
               
                   
                 231 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 232 
               
               
                   
                 232 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 233 
               
               
                   
                 233 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 234 
               
               
                   
                 234 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 235 
               
               
                   
                 235 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 236 
               
               
                   
                 236 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 237 
               
               
                   
                 237 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 238 
               
               
                   
                 238 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 239 
               
               
                   
                 239 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 240 
               
               
                   
                 240 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 241 
               
               
                   
                 241 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 242 
               
               
                   
                 242 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 243 
               
               
                   
                 243 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 244 
               
               
                   
                 244 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 245 
               
               
                   
                 245 
                 Q 
                 K 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 246 
               
               
                   
                 246 
                 Q 
                 H 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 247 
               
               
                   
                 247 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 248 
               
               
                   
                 248 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 249 
               
               
                   
                 249 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 250 
               
               
                   
                 250 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 251 
               
               
                   
                 251 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 252 
               
               
                   
                 252 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 253 
               
               
                   
                 253 
                 Km 
                 K 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 254 
               
               
                   
                 254 
                 Km 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 255 
               
               
                   
                 255 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 256 
               
               
                   
                 256 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 257 
               
               
                   
                 257 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 258 
               
               
                   
                 258 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 259 
               
               
                   
                 259 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 260 
               
               
                   
                 260 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 261 
               
               
                   
                 261 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 262 
               
               
                   
                 262 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 263 
               
               
                   
                 263 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 264 
               
               
                   
                 264 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 265 
               
               
                   
                 265 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 266 
               
               
                   
                 266 
                 Q 
                 S 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 267 
               
               
                   
                 267 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 268 
               
               
                   
                 268 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 269 
               
               
                   
                 269 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 OH 
                 270 
               
               
                   
                 270 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 271 
               
               
                   
                 271 
                 Q 
                 Km 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 272 
               
               
                   
                 272 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 273 
               
               
                   
                 273 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 274 
               
               
                   
                 274 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 275 
               
               
                   
                 275 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 276 
               
               
                   
                 276 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 277 
               
               
                   
                 277 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 278 
               
               
                   
                 278 
                 Km 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 279 
               
               
                   
                 279 
                 Q 
                 R 
                 G 
                 OH 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                 280 
               
               
                   
                 280 
                 Km 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 281 
               
               
                   
                 281 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 282 
               
               
                   
                 282 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 283 
               
               
                   
                 283 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 284 
               
               
                   
                 284 
                 Q 
                 S 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 285 
               
               
                   
                 285 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 286 
               
               
                   
                 286 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 287 
               
               
                   
                 287 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 288 
               
               
                   
                 288 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 289 
               
               
                   
                 289 
                 Q 
                 K 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 290 
               
               
                   
                 290 
                 Q 
                 R 
                 NH2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 291 
               
               
                   
                 291 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 K 
                 K 
                 K 
                 K 
                 K 
                 K 
                 NH2 
                 292 
               
               
                   
                 292 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 K 
                 K 
                 K 
                 K 
                 K 
                 K 
                 NH2 
                 293 
               
               
                   
                 293 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 294 
               
               
                   
                 294 
                 Q 
                 N 
                 G 
                 G 
                 G 
                 G 
                 G 
                 
                   
                 
                 NH2 
                   
                   
                   
                 295 
               
               
                   
                 295 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 296 
               
               
                   
                 296 
                 Q 
                 S 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 297 
               
               
                   
                 297 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 298 
               
               
                   
                 298 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 299 
               
               
                   
                 299 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 300 
               
               
                   
                 300 
                 Q 
                 R 
                 P 
                 S 
                 S 
                 G 
                 A 
                 P 
                 P 
                 P 
                 S 
                 NH2 
                 301 
               
               
                   
                 301 
                 Q 
                 R 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 302 
               
               
                   
                 302 
                 Q 
                 K 
                 G 
                 OH 
                   
                   
                   
                   
                   
                   
                   
                   
                 303 
               
               
                   
                 303 
                 Q 
                 K 
                 G 
                 K 
                 K 
                 N 
                 D 
                 W 
                 K 
                 N 
                 N 
                 I 
                 304 
               
               
                   
                 304 
                 Q 
                 K 
                 G 
                 OH 
               
               
                   
                 305 
                 Q 
                 R 
                 G 
                 OH 
               
               
                   
                   
               
               
                   
                 N-TER means N-terminus; 
               
               
                   
                 C-TER means C-terminus; 
               
               
                   
                 C15DA means C 15  diacid; 
               
               
                   
                 C16DA means C 16  diacid 
               
               
                   
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Biological Examples 
     Methods for performing GIP and GLP receptor binding assays, assays for inhibition of emesis, vomiting and nausea, caused by various stimuli, including from drug or chemotherapy induced emesis are specifically described in Applicant&#39;s International PCT Application No. PCT/JP2018/013540, filed on Mar. 30, 2018, ranging from pages 213 to 255, and are specifically incorporated herein by reference in their entirety. 
     Example 8-Evaluation of Peptide Agonist Activity on Human GIPR and Human GLP1R by Measuring Intracellular cAMP Accumulation 
     GIPR Assay 
     HEK-293T cells overexpressing full-length human GIPR with a sequence identical to GenBank accession number NM_000164 with an N-terminal FLAG tag are purchased from Multispan, Inc (Hayward, Calif.). Cells are cultured per the manufacturer&#39;s protocol in DMEM with 10% fetal bovine serum and 1 μg/mL puromycin and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells are removed from frozen storage, washed two times in 1× Kreb&#39;s Ringer Buffer (Zenbio, Research Triangle Park, N.C.), and re-suspended to a concentration of 4×10 5  cells/mL in 1× Kreb&#39;s Ringer Buffer. 50 nL of test compound in 100% DMSO spanning a final concentration range of 3×10 −10 -5.08×10 −15  M are acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, Mass.), followed by the addition of 4×10 3  cells per well in total volume of 10 μL. Cells are incubated with test compound for 1 hr at room temperature in the dark, and cAMP accumulation is measured using the Cisbio HiRange cAMP assay kit (Bedford, Mass.) per the manufacturer&#39;s protocol. Anti-cAMP antibody and d2-cAMP tracer reagents diluted in lysis/detection buffer are incubated in the dark for 1 hr, and results are measured on an Envision plate reader (Perkin Elmer, Waltham, Mass.). Data is normalized using 1 nM GIP as 100% activity, and DMSO alone as 0% activity. 
     HEK-293T cells overexpressing full-length human GLP-1R with a sequence identical to GenBank accession number NM_002062 with an N-terminal FLAG tag may be purchased from Multispan, Inc (Hayward, Calif.). Cells are cultured per the manufacturer&#39;s protocol in DMEM with 100 fetal bovine serum and 1 μg/mL puromycin and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells are removed from frozen storage, washed two times in 1× Kreb&#39;s Ringer Buffer (Zenbio, Research Triangle Park, N.C.), and re-suspended to a concentration of 4×10 5  cells/mL in 1× Kreb&#39;s Ringer Buffer. 50 nL of test compound in 100% DMSO spanning a final concentration range of 1×10 −6 -1.69×10 −11  M are acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, Mass.), followed by the addition of 4×10 3  cells per well in total volume of 10 μL. Cells are incubated with test compound for 1 hr at room temperature in the dark, and cAMP accumulation is measured using the Cisbio HiRange cAMP assay kit (Bedford, Mass.) per the manufacturer&#39;s protocol. Anti-cAMP antibody and d2-cAMP tracer reagents diluted in lysis/detection buffer are incubated in the dark for 1 hr, and results are measured on an Envision plate reader (Perkin Elmer, Waltham, Mass.). Data is normalized using 1 nM GLP-1 as 100% activity, and DMSO alone as 0% activity. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 GIP receptor selective activation of various GIP 
               
               
                 receptor agonist peptides of the disclosure 
               
            
           
           
               
               
               
               
            
               
                 Compound 
                 Sequence 
                 Human GIPR cAMP, 
                 Human GLP1R cAMP 
               
               
                 No. 
                 ID No. 
                 HEK293T EC50 (nM) 
                 HEK293T EC50 (nM) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 2 
                 0.0002 
                 870.9636 
               
               
                 2 
                 3 
                 0.0001 
                 1000 
               
               
                 3 
                 4 
                 0.0004 
                 691.831 
               
               
                 4 
                 5 
                 0.0005 
                 691.831 
               
               
                 5 
                 6 
                 0.0008 
                 954.9926 
               
               
                 6 
                 7 
                 0.0537 
                 691.831 
               
               
                 7 
                 8 
                 0.0016 
                 257.0396 
               
               
                 8 
                 9 
                 0.0001 
                 100 
               
               
                 9 
                 10 
                 0.0002 
                 95.4993 
               
               
                 10 
                 11 
                 0.0006 
                 954.9926 
               
               
                 11 
                 12 
                 0.0003 
                 144.544 
               
               
                 12 
                 13 
                 0.0002 
                 363.0781 
               
               
                 13 
                 14 
                 0.0002 
                 142.8894 
               
               
                 14 
                 15 
                 0.0004 
                 61.0942 
               
               
                 15 
                 16 
                 0.0003 
                 154.8817 
               
               
                 16 
                 17 
                 0.0003 
                 263.0268 
               
               
                 17 
                 18 
                 0.0004 
                 160.3245 
               
               
                 18 
                 19 
                 0.0002 
                 1000 
               
               
                 19 
                 20 
                 0.0004 
                 119.3072 
               
               
                 20 
                 21 
                 0.0003 
                 116.1449 
               
               
                 21 
                 22 
                 0.0003 
                 152.5223 
               
               
                 22 
                 23 
                 0.0003 
                 630.9573 
               
               
                 23 
                 24 
                 0.0004 
                 363.0781 
               
               
                 24 
                 25 
                 0.0004 
                 16.8526 
               
               
                 25 
                 26 
                 0.0005 
                 37.368 
               
               
                 26 
                 27 
                 0.0003 
                 1000 
               
               
                 27 
                 28 
                 0.0006 
                 144.544 
               
               
                 28 
                 29 
                 0.0001 
                 60.256 
               
               
                 29 
                 30 
                 0.0001 
                 47.1339 
               
               
                 30 
                 31 
                 0.0001 
                 441.5704 
               
               
                 31 
                 32 
                 0.0002 
                 0.7762 
               
               
                 32 
                 33 
                 0.0002 
                 4.7315 
               
               
                 33 
                 34 
                 0.0002 
                 37.5837 
               
               
                 34 
                 35 
                 0.0003 
                 117.4898 
               
               
                 35 
                 36 
                 0.0003 
                 67.6083 
               
               
                 36 
                 37 
                 0.001 
                 25.1189 
               
               
                 37 
                 38 
                 0.0002 
                 43.6516 
               
               
                 38 
                 39 
                 0.0002 
                 524.8075 
               
               
                 39 
                 40 
                 0.0005 
                 398.1072 
               
               
                 40 
                 41 
                 0.0008 
                 114.8154 
               
               
                 41 
                 42 
                 0.0004 
                 112.2018 
               
               
                 42 
                 43 
                 0.0006 
                 237.1374 
               
               
                 43 
                 44 
                 0.0003 
                 173.7801 
               
               
                 44 
                 45 
                 0.0004 
                 630.9573 
               
               
                 45 
                 46 
                 0.0003 
                 48.4172 
               
               
                 46 
                 47 
                 0.0002 
                 0.1445 
               
               
                 47 
                 48 
                 0.0003 
                 109.6478 
               
               
                 48 
                 49 
                 0.0002 
                 47.863 
               
               
                 49 
                 50 
                 0.0002 
                 794.3282 
               
               
                 50 
                 51 
                 0.0004 
                 44.6684 
               
               
                 51 
                 52 
                 0.0003 
                 1000 
               
               
                 52 
                 53 
                 0.0003 
                 239.8833 
               
               
                 53 
                 54 
                 0.0001 
                 616.595 
               
               
                 54 
                 55 
                 0.0001 
                 446.6836 
               
               
                 55 
                 56 
                 0.0002 
                 239.8833 
               
               
                 56 
                 57 
                 0.0003 
                 263.0268 
               
               
                 59 
                 60 
                 0.0004 
                 56.2341 
               
               
                 63 
                 64 
                 0.0002 
                 141.2538 
               
               
                 64 
                 65 
                 0.0005 
                 1000 
               
               
                 65 
                 66 
                 0.0003 
                 128.825 
               
               
                 66 
                 67 
                 0.0004 
                 1000 
               
               
                 67 
                 68 
                 0.0006 
                 524.8075 
               
               
                 68 
                 69 
                 0.0007 
                 199.5262 
               
               
                 69 
                 70 
                 0.0004 
                 1000 
               
               
                 70 
                 71 
                 0.0009 
                 91.2011 
               
               
                 71 
                 72 
                 0.0006 
                 954.9926 
               
               
                 72 
                 73 
                 0.0006 
                 190.5461 
               
               
                 73 
                 74 
                 0.0005 
                 1000 
               
               
                 74 
                 75 
                 0.0004 
                 549.5409 
               
               
                 75 
                 76 
                 0.0011 
                 1000 
               
               
                 76 
                 77 
                 0.0005 
                 295.1209 
               
               
                 77 
                 78 
                 0.0002 
                 331.1311 
               
               
                 78 
                 79 
                 0.0003 
                 112.2018 
               
               
                 79 
                 80 
                 0.0002 
                 707.9458 
               
               
                 80 
                 81 
                 0.0004 
                 467.7351 
               
               
                 81 
                 82 
                 0.0002 
                 1000 
               
               
                 82 
                 83 
                 0.0003 
                 295.1209 
               
               
                 84 
                 85 
                 0.0012 
                 371.5352 
               
               
                 85 
                 86 
                 0.0009 
                 63.0957 
               
               
                 86 
                 87 
                 0.0014 
                 93.3254 
               
               
                 87 
                 88 
                 0.0009 
                 199.5262 
               
               
                 88 
                 89 
                 0.0006 
                 165.9587 
               
               
                 89 
                 90 
                 0.0006 
                 83.1764 
               
               
                 90 
                 91 
                 0.0007 
                 295.1209 
               
               
                 91 
                 92 
                 0.0008 
                 125.8925 
               
               
                 92 
                 93 
                 0.0013 
                 74.131 
               
               
                 93 
                 94 
                 0.0002 
                 489.7788 
               
               
                 94 
                 95 
                 0.0006 
                 501.1872 
               
               
                 95 
                 96 
                 0.0002 
                 537.0318 
               
               
                 96 
                 97 
                 0.0004 
                 89.1251 
               
               
                 97 
                 98 
                 0.0002 
                 489.7788 
               
               
                 98 
                 99 
                 0.0006 
                 1000 
               
               
                 99 
                 100 
                 0.0002 
                 1000 
               
               
                 100 
                 101 
                 0.0007 
                 1000 
               
               
                 101 
                 102 
                 0.0002 
                 549.5409 
               
               
                 102 
                 103 
                 0.0005 
                 31.6228 
               
               
                 103 
                 104 
                 0.0005 
                 147.9108 
               
               
                 104 
                 105 
                 0.0004 
                 1000 
               
               
                 105 
                 106 
                 0.0003 
                 1000 
               
               
                 106 
                 107 
                 0.0005 
                 120.2264 
               
               
                 107 
                 108 
                 0.0008 
                 891.2509 
               
               
                 108 
                 109 
                 0.0005 
                 41.6869 
               
               
                 109 
                 110 
                 0.0005 
                 831.7638 
               
               
                 110 
                 111 
                 0.0004 
                 323.5937 
               
               
                 111 
                 112 
                 0.0004 
                 7.0795 
               
               
                 112 
                 113 
                 0.0004 
                 12.0226 
               
               
                 113 
                 114 
                 0.0004 
                 44.6684 
               
               
                 114 
                 115 
                 0.0007 
                 114.8154 
               
               
                 115 
                 116 
                 0.0005 
                 436.5158 
               
               
                 116 
                 117 
                 0.0003 
                 338.8442 
               
               
                 117 
                 118 
                 0.0006 
                 1000 
               
               
                 118 
                 119 
                 0.0009 
                 524.8075 
               
               
                 119 
                 120 
                 0.0005 
                 1000 
               
               
                 120 
                 121 
                 0.0004 
                 5.2481 
               
               
                 121 
                 122 
                 0.0003 
                 5.4954 
               
               
                 122 
                 123 
                 0.0004 
                 20.4174 
               
               
                 123 
                 124 
                 0.0004 
                 22.9087 
               
               
                 124 
                 125 
                 0.004 
                 125.8925 
               
               
                 125 
                 126 
                 0.0002 
                 165.9587 
               
               
                 126 
                 127 
                 0.0002 
                 588.8437 
               
               
                 127 
                 128 
                 0.0005 
                 66.0693 
               
               
                 128 
                 129 
                 0.0004 
                 457.0882 
               
               
                 129 
                 130 
                 0.0005 
                 1000 
               
               
                 130 
                 131 
                 0.0004 
                 91.2011 
               
               
                 131 
                 132 
                 0.0003 
                 75.8578 
               
               
                 132 
                 133 
                 0.0001 
                 21.8776 
               
               
                 133 
                 134 
                 0.0005 
                 1000 
               
               
                 134 
                 135 
                 0.0004 
                 1000 
               
               
                 135 
                 136 
                 0.0005 
                 645.6542 
               
               
                 136 
                 137 
                 0.0009 
                 407.3803 
               
               
                 137 
                 138 
                 0.0002 
                 478.6301 
               
               
                 138 
                 139 
                 0.0004 
                 1000 
               
               
                 139 
                 140 
                 0.0004 
                 1000 
               
               
                 140 
                 141 
                 0.0004 
                 177.8279 
               
               
                 141 
                 142 
                 0.0003 
                 64.5654 
               
               
                 142 
                 143 
                 0.0001 
                 84.1395 
               
               
                 143 
                 144 
                 0.0004 
                 141.2538 
               
               
                 144 
                 145 
                 0.0001 
                 18.8365 
               
               
                 145 
                 146 
                 0.0004 
                 912.0108 
               
               
                 146 
                 147 
                 0.0005 
                 112.2018 
               
               
                 147 
                 148 
                 0.0011 
                 16.5959 
               
               
                 148 
                 149 
                 0.0011 
                 13.8038 
               
               
                 149 
                 150 
                 0.0007 
                 25.704 
               
               
                 150 
                 151 
                 0.0003 
                 30.1995 
               
               
                 151 
                 152 
                 0.0004 
                 144.544 
               
               
                 152 
                 153 
                 0.0003 
                 301.9952 
               
               
                 153 
                 154 
                 0.0002 
                 389.0451 
               
               
                 154 
                 155 
                 0.0003 
                 288.4032 
               
               
                 155 
                 156 
                 0.0003 
                 295.1209 
               
               
                 156 
                 157 
                 0.0002 
                 89.1251 
               
               
                 157 
                 158 
                 0.0001 
                 346.7368 
               
               
                 158 
                 159 
                 0.0002 
                 245.4709 
               
               
                 159 
                 160 
                 0.0002 
                 144.544 
               
               
                 160 
                 161 
                 0.0003 
                 23.9883 
               
               
                 161 
                 162 
                 0.0003 
                 &gt;1000.0000 
               
               
                 162 
                 163 
                 0.0002 
                 512.8614 
               
               
                 163 
                 164 
                 0.0003 
                 &gt;1000.0000 
               
               
                 164 
                 165 
                 0.0002 
                 9.7724 
               
               
                 165 
                 166 
                 0.0004 
                 85.1138 
               
               
                 166 
                 167 
                 0.0004 
                 89.1251 
               
               
                 167 
                 168 
                 0.0004 
                 41.6869 
               
               
                 168 
                 169 
                 0.0003 
                 17.378 
               
               
                 169 
                 170 
                 0.0006 
                 &gt;1000.0000 
               
               
                 170 
                 171 
                 0.0004 
                 &gt;1000.0000 
               
               
                 171 
                 172 
                 0.0005 
                 &gt;1000.0000 
               
               
                 172 
                 173 
                 0.0004 
                 64.5654 
               
               
                 173 
                 174 
                 0.0005 
                 &gt;1000.0000 
               
               
                 174 
                 175 
                 0.0003 
                 10.7152 
               
               
                 175 
                 176 
                 0.0004 
                 44.6684 
               
               
                 176 
                 177 
                 0.0004 
                 89.1251 
               
               
                 177 
                 178 
                 0.0002 
                 1000 
               
               
                 180 
                 181 
                 0.0003 
                 &gt;1000.0000 
               
               
                 181 
                 182 
                 0.0004 
                 162.181 
               
               
                 182 
                 183 
                 0.0002 
                 154.8817 
               
               
                 183 
                 184 
                 0.0005 
                 89.1251 
               
               
                 184 
                 185 
                 0.0003 
                 &gt;1000.0000 
               
               
                 185 
                 186 
                 0.0004 
                 &gt;1000.0000 
               
               
                 186 
                 187 
                 0.0003 
                 26.9153 
               
               
                 187 
                 188 
                 0.0002 
                 51.2861 
               
               
                 188 
                 189 
                 0.0003 
                 22.9087 
               
               
                 189 
                 190 
                 0.0003 
                 15.4882 
               
               
                 190 
                 191 
                 0.0158 
                 1000 
               
               
                 191 
                 192 
                 0.0049 
                 0.0058 
               
               
                 192 
                 193 
                 0.1479 
                 741.3102 
               
               
                 193 
                 194 
                 0.0741 
                 17.7828 
               
               
                 194 
                 195 
                 0.0389 
                 125.8925 
               
               
                 195 
                 196 
                 0.0708 
                 1000 
               
               
                 196 
                 197 
                 0.0002 
                 691.831 
               
               
                 201 
                 202 
                 0.0002 
                 9.1201 
               
               
                 202 
                 203 
                 0.0003 
                 14.7911 
               
               
                 203 
                 204 
                 0.003 
                 2.6303 
               
               
                 204 
                 205 
                 0.0008 
                 3.0903 
               
               
                 205 
                 206 
                 0.0002 
                 13.4896 
               
               
                 206 
                 207 
                 0.0013 
                 144.544 
               
               
                 207 
                 208 
                 0.0004 
                 9.3325 
               
               
                 208 
                 209 
                 0.0003 
                 57.544 
               
               
                 209 
                 210 
                 0.0003 
                 478.6301 
               
               
                 210 
                 211 
                 0.0003 
                 128.825 
               
               
                 211 
                 212 
                 0.0002 
                 173.7801 
               
               
                 212 
                 213 
                 0.0002 
                 66.0693 
               
               
                 213 
                 214 
                 0.0003 
                 16.9824 
               
               
                 214 
                 215 
                 0.0003 
                 56.2341 
               
               
                 215 
                 216 
                 0.0002 
                 45.7088 
               
               
                 216 
                 217 
                 0.0003 
                 34.6737 
               
               
                 217 
                 218 
                 0.0002 
                 4.8978 
               
               
                 218 
                 219 
                 0.0006 
                 89.1251 
               
               
                 219 
                 220 
                 0.0004 
                 6.7608 
               
               
                   
               
            
           
         
       
     
     Table 4 provides the selective binding activity of the GIPR agonist peptides of the present disclosure. As can be seen, the peptide compounds provided here have a human GLP1R cAMP EC 50 /human GIPR cAMP EC 50  ratios ranging from about 800 to about 10,000,000, thus indicating incredibly selective GIPR agonist binding activity. Most of the GIPR agonist peptide compounds display Human GLP1R cAMP EC 50 /Human GIPR cAMP EC 50  ratios of greater than 1,000, or greater than 5,000, or greater than 10,000, or greater than 50,000, or greater than 100,000, or greater than 500,000. 
     Example 9. Oral Glucose Tolerance Test 
     An oral glucose tolerance test (OGTT) was carried out using C57BL/6J mice with a glucose load of 2.5 g/kg by oral administration. Testing concentrations of 0.1, 0.3 or 3 nmol/kg were selected depending on the peptide. Each peptide or a vehicle (control group) was subcutaneously administered 30 mi before glucose loading and the blood glucose levels were measured at 15, 30, 60 and 120 min post oral glucose administration to evaluate the action of the compound. The action of the compound was calculated by the calculation formula below and expressed as the 0% drop in glucose as measured over 120 min using AUC. 
       % inhibition=(1−(AUC cpd/AUC vehicle))×100.
 
     Results are shown in Table 5. As shown in Table 5, it is verified that the compounds of the present invention suppress increase in blood glucose level caused by oral glucose loading. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 oral glucose tolerance test 
               
            
           
           
               
               
               
            
               
                   
                   
                 Oral Glucose Tolerance Test 
               
               
                   
                   
                 Percent decrease of blood 
               
               
                 Compound 
                 Sequence 
                 glucose AUC (%) over 120 mins 
               
               
                 No. 
                 ID No. 
                 at different compound doses (nmol/kg) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 14 
                 15 
                 23% (0.1 nmol/kg), 
               
               
                   
                   
                 37% (3 nmol/kg) 
               
               
                 17 
                 18 
                 24% (0.1 nmol/kg), 
               
               
                   
                   
                 39% (3 nmol/kg) 
               
               
                 18 
                 19 
                 29% (3 nmol/kg) 
               
               
                 19 
                 20 
                 38% (3 nmol/kg) 
               
               
                 20 
                 21 
                 42% (3 nmol/kg) 
               
               
                 21 
                 22 
                 29% (0.1 nmol/kg), 
               
               
                   
                   
                 36% (0.3 nmol/kg), 
               
               
                   
                   
                 44% (3 nmol/kg) 
               
               
                 24 
                 25 
                 40% (3 nmol/kg) 
               
               
                 25 
                 26 
                 28% (0.1 nmol/kg), 
               
               
                   
                   
                 33% (0.3 nmol/kg)/kg, 
               
               
                   
                   
                 41% (3 nmol/kg) 
               
               
                 29 
                 30 
                 20% (0.1 nmol/kg) 
               
               
                 30 
                 31 
                 30% (3 nmol/kg) 
               
               
                 31 
                 32 
                 20% (0.1 nmol/kg) 
               
               
                 32 
                 33 
                 35% (3 nmol/kg) 
               
               
                 33 
                 34 
                 34% (3 nmol/kg) 
               
               
                 34 
                 35 
                 38% (3 nmol/kg) 
               
               
                 37 
                 38 
                 44% (3 nmol/kg) 
               
               
                 41 
                 42 
                 12% (0.1 nmol/kg) 
               
               
                 42 
                 43 
                 35% (3 nmol/kg) 
               
               
                 43 
                 44 
                 39% (3 nmol/kg) 
               
               
                 44 
                 45 
                 42% (3 nmol/kg) 
               
               
                 45 
                 46 
                 39% (3 nmol/kg) 
               
               
                 48 
                 49 
                 22% (0.1 nmol/kg), 
               
               
                   
                   
                 35% (0.3 nmol/kg), 
               
               
                   
                   
                 43% (3 nmol/kg) 
               
               
                 49 
                 50 
                 29% (3 nmol/kg) 
               
               
                 50 
                 51 
                 41% (3 nmol/kg) 
               
               
                 52 
                 53 
                 34% (3 nmol/kg) 
               
               
                 54 
                 55 
                 14% (0.1 nmol/kg) 
               
               
                 55 
                 56 
                 36% (3 nmol/kg) 
               
               
                 58 
                 59 
                 17% (0.1 nmol/kg) 
               
               
                 60 
                 61 
                 06% (0.1 nmol/kg) 
               
               
                 63 
                 64 
                 10% (0.1 nmol/kg) 
               
               
                 65 
                 66 
                 21% (0.1 nmol/kg) 
               
               
                 68 
                 69 
                 24% (0.1 nmol/kg) 
               
               
                 69 
                 70 
                 18% (0.1 nmol/kg) 
               
               
                 70 
                 71 
                 23% (0.1 nmol/kg) 
               
               
                 71 
                 72 
                 24% (0.1 nmol/kg) 
               
               
                 72 
                 73 
                 28% (0.1 nmol/kg) 
               
               
                 74 
                 75 
                 27% (0.1 nmol/kg) 
               
               
                 75 
                 76 
                 24% (0.1 nmol/kg) 
               
               
                 78 
                 79 
                 28% (0.1 nmol/kg) 
               
               
                 83 
                 84 
                 26% (0.1 nmol/kg) 
               
               
                 84 
                 85 
                 14% (0.1 nmol/kg) 
               
               
                 87 
                 88 
                 19% (0.1 nmol/kg) 
               
               
                 88 
                 89 
                 14% (0.1 nmol/kg) 
               
               
                 90 
                 91 
                 06% (0.1 nmol/kg) 
               
               
                 91 
                 92 
                 00% (0.1 nmol/kg) 
               
               
                 92 
                 93 
                 18% (0.1 nmol/kg) 
               
               
                 93 
                 94 
                 36% (0.1 nmol/kg) 
               
               
                   
                   
                 39% (0.3 nmol/kg) 
               
               
                 96 
                 97 
                 31% (0.1 nmol/kg) 
               
               
                 98 
                 99 
                 09% (0.1 nmol/kg) 
               
               
                 100 
                 101 
                 11% (0.1 nmol/kg) 
               
               
                 101 
                 102 
                 27% (0.1 nmol/kg) 
               
               
                 102 
                 103 
                 37% (0.1 nmol/kg) 
               
               
                 103 
                 104 
                 32% (0.1 nmol/kg) 
               
               
                 106 
                 107 
                 26% (0.1 nmol/kg) 
               
               
                 107 
                 108 
                 25% (0.1 nmol/kg) 
               
               
                 108 
                 109 
                 28% (0.1 nmol/kg) 
               
               
                 109 
                 110 
                 13% (0.1 nmol/kg) 
               
               
                 111 
                 112 
                 31% (0.1 nmol/kg) 
               
               
                 114 
                 115 
                 28% (0.1 nmol/kg) 
               
               
                 117 
                 118 
                 11% (0.1 nmol/kg) 
               
               
                 121 
                 122 
                 01% (0.1 nmol/kg) 
               
               
                 123 
                 124 
                 10% (0.1 nmol/kg) 
               
               
                 124 
                 125 
                 12% (0.1 nmol/kg) 
               
               
                 131 
                 132 
                 36% (0.1 nmol/kg) 
               
               
                 132 
                 133 
                 38% (0.1 nmol/kg) 
               
               
                   
                   
                 33% (0.3 nmol/kg) 
               
               
                 133 
                 134 
                 35% (0.1 nmol/kg) 
               
               
                 136 
                 137 
                 23% (0.1 nmol/kg) 
               
               
                 140 
                 141 
                 21% (0.1 nmol/kg) 
               
               
                 141 
                 142 
                 10% (0.1 nmol/kg) 
               
               
                 142 
                 143 
                 33% (0.1 nmol/kg), 
               
               
                   
                   
                 21 and 28% (0.3 nmol/kg) 
               
               
                 143 
                 144 
                 13% (0.1 nmol/kg) 
               
               
                 144 
                 145 
                 26% (0.1 nmol/kg), 
               
               
                   
                   
                 25% (0.3 nmol/kg) 
               
               
                 146 
                 147 
                 30% (0.1 nmol/kg) 
               
               
                 147 
                 148 
                 28% (0.1 nmol/kg) 
               
               
                 148 
                 149 
                 045 and 042% (3 nmol/kg) 
               
               
                 149 
                 150 
                 20% (0.1 nmol/kg) 
               
               
                 150 
                 151 
                 23% (0.1 nmol/kg) 
               
               
                 151 
                 152 
                 24% (0.1 nmol/kg) 
               
               
                 152 
                 153 
                 18% (0.1 nmol/kg) 
               
               
                 153 
                 154 
                 21% (0.1 nmol/kg) 
               
               
                 154 
                 155 
                 18% (0.1 nmol/kg) 
               
               
                 155 
                 156 
                 18% (0.1 nmol/kg) 
               
               
                 156 
                 157 
                 31% (0.1 nmol/kg) 
               
               
                 157 
                 158 
                 20% (0.1 nmol/kg) 
               
               
                 158 
                 159 
                 20% (0.1 nmol/kg) 
               
               
                 159 
                 160 
                 32% (0.1 nmol/kg) 
               
               
                   
                   
                 18% (0.3 nmol/kg) 
               
               
                 160 
                 161 
                 20% (0.1 nmol/kg) 
               
               
                 162 
                 163 
                 00% (0.1 nmol/kg) 
               
               
                 164 
                 165 
                 34% (0.1 nmol/kg) 
               
               
                 165 
                 166 
                 29% (0.1 nmol/kg) 
               
               
                 166 
                 167 
                 12% (0.1 nmol/kg) 
               
               
                 167 
                 168 
                 34% (0.1 nmol/kg) 
               
               
                 169 
                 170 
                 10% (0.1 nmol/kg) 
               
               
                 171 
                 172 
                 23% (0.1 nmol/kg) 
               
               
                 173 
                 174 
                 14% (0.1 nmol/kg) 
               
               
                 175 
                 176 
                 17% (0.1 nmol/kg), 
               
               
                   
                   
                 25% (0.3 nmol/kg) 
               
               
                 176 
                 177 
                 14% (0.1 nmol/kg), 
               
               
                   
                   
                 16% (0.3 nmol/kg) 
               
               
                 177 
                 178 
                 18% (0.1 nmol/kg) 
               
               
                 178 
                 179 
                 11% (0.1 nmol/kg) 
               
               
                 180 
                 181 
                 18% (0.1 nmol/kg) 
               
               
                 181 
                 182 
                 02% (0.1 nmol/kg) 
               
               
                 182 
                 183 
                 09% (0.1 nmol/kg) 
               
               
                 183 
                 184 
                 24% (0.1 nmol/kg) 
               
               
                 184 
                 185 
                 32% (0.1 nmol/kg) 
               
               
                 185 
                 186 
                 08% (0.1 nmol/kg) 
               
               
                 186 
                 187 
                 07% (0.1 nmol/kg) 
               
               
                 187 
                 188 
                 30% (0.1 nmol/kg), 
               
               
                   
                   
                 38% (0.3 nmol/kg) 
               
               
                   
               
            
           
         
       
     
     As shown in Table 5, the GIPR agonist peptide compounds of the present invention with a 20% or greater decrease in blood glucose suppress increase in blood glucose level caused by oral glucose loading. 
     Example 10: PYY-1119-Induced Vomiting in Dogs 
     Effects of single subcutaneous administration of the GIPR agonist compounds of the present disclosure on Neuropeptide Y2 receptor (Y2R) agonist compound PYY-1119 (4-imidazolecarbonyl-Ser-D-Hyp-Iva-Pya(4)-Cha-Leu(Me)-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Cha-NH2) (10 μg/kg [about 5 nmol/kg], s.c.) induced emesis were evaluated in dogs. The GIPR agonist peptide compounds of the present disclosure or vehicle (0.09% [w/v] Tween 80/10% DMSO/PBS) was administered subcutaneously (sc) at different doses to female beagle dogs (10 months old), followed by sc injections with Y2R agonist ((4-imidazolecarbonyl-Ser-D-Hyp-Iva-Pya(4)-Cha-Leu(Me)-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Cha-NH2), 10 μg/kg), 10 μg/kg) at 1 hour or specified hours in the table postdose. Emetic episodes were counted for 2 hours after administration (by blinded analysis). 
     Table 6 shows the compounds suppressed the PYY-1119-induced emetic symptoms. In the below table, results are shown as percent inhibition (%) at the dose of compound (nmol/kg) shown, at the hour(s) postdose of PYY-1119, calculated as (1−(number of emetic episodes with peptide compound/number of emetic episodes with vehicle))×100. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Percent inhibition of emetic episodes in dogs 
               
               
                 treated with the peptide compounds of the present 
               
               
                 disclosure when challenged with PYY-1119. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Inhibition percent (%) of 
               
               
                   
                   
                   
                 PYY-1119-induced emetic 
               
               
                   
                 Compound 
                 SEQ 
                 symptoms at 1 hour (or *72 hours) 
               
               
                   
                 No. 
                 ID No. 
                 postdose at different compound dose 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 14 
                 15 
                 91% (3 nmol/kg) 
               
               
                   
                 17 
                 18 
                 100% (3 nmol/kg) 
               
               
                   
                 19 
                 20 
                 86% (3 nmol/kg) 
               
               
                   
                 20 
                 21 
                 96% (3 nmol/kg) 
               
               
                   
                   
                   
                 82% (3 nmol/kg) *72 hr 
               
               
                   
                 21 
                 22 
                 96% (3 nmol/kg) 
               
               
                   
                 24 
                 25 
                 81% (3 nmol/kg) 
               
               
                   
                 25 
                 26 
                 100% (3 nmol/kg) 
               
               
                   
                   
                   
                 92% (1 nmol/kg) 
               
               
                   
                   
                   
                 58% (0.3 nmol/kg) 
               
               
                   
                 43 
                 44 
                 83% (3 nmol/kg) 
               
               
                   
                 44 
                 45 
                 90% (10 nmol/kg) 
               
               
                   
                 48 
                 49 
                 96.3% (3 nmol/kg) 
               
               
                   
                 50 
                 51 
                 100% (10 nmol/kg) 
               
               
                   
                 54 
                 55 
                 43% (1 nmol/kg) 
               
               
                   
                 55 
                 56 
                 86% (3 nmol/kg) 
               
               
                   
                 58 
                 59 
                 93.8% (3 nmol/kg) 
               
               
                   
                 60 
                 61 
                 57% (1 nmol/kg) 
               
               
                   
                 72 
                 73 
                 98% (1 nmol/kg) 
               
               
                   
                 78 
                 79 
                 96% (1 nmol/kg) 
               
               
                   
                 96 
                 97 
                 90% (1 nmol/kg) 
               
               
                   
                 132 
                 133 
                 68% (1 nmol/kg) 
               
               
                   
                 140 
                 141 
                 63% (1 nmol/kg) 
               
               
                   
                 142 
                 143 
                 63% (1 nmol/kg) 
               
               
                   
                   
                   
                 92% (3 nmol/kg) 
               
               
                   
                 144 
                 145 
                 89% (3 nmol/kg); 
               
               
                   
                   
                   
                 70% (1 nmol/kg); 
               
               
                   
                   
                   
                 62% (3 nmol/kg) *72 h 
               
               
                   
                 148 
                 149 
                 88% (3 nmol/kg) 
               
               
                   
                   
                   
                 78% (3 nmol/kg) *72 hr, 
               
               
                   
                 159 
                 160 
                 59% (1 nmol/kg) 
               
               
                   
                 182 
                 183 
                 71% (1 nmol/kg) 
               
               
                   
                 183 
                 184 
                 79% (1 nmol/kg) 
               
               
                   
                 184 
                 185 
                 79% (1 nmol/kg) 
               
               
                   
                   
               
            
           
         
       
     
     As shown in Table 6, it is verified that the compounds of the present invention inhibited PYY-1119 induced emesis, including symptoms of vomiting. 
     Table 7 shows the effect of Compound 14 on PYY (T-481, 10 μg/kg, s.c.) induced vomiting in dogs. The results are also shown in  FIG. 2 . 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Effect of Test Peptides on T-481 (10 μg/kg, s.c.)-induced vomiting in 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Doses 
                 No. of 
                 Emesis 
                   
                   
                   
               
               
                 T-481 was 
                 Compound 
                 (nmol/kg, 
                 animals 
                 response a   
                 Latency b   
                 Duration c   
                 Inhibition 
               
               
                 administered 
                 No. 
                 s.c.) 
                 (responder/used) 
                 (counts) 
                 (min) 
                 (min) 
                 (%) 
               
               
                   
               
               
                 8 h after 
                 Vehicle d   
                 — 
                 4/4 
                 13.0 ± 1.5    
                 6.5 ± 0.9     
                 67.3 ± 14.1    
                   
               
               
                   
                 14 
                 1 
                 1/4 
                 0.3 ± 0.3 *** 
                 93.7 ± 26.3 * 
                 0.1 ± 0.1 *** 
                 97.7 
               
               
                   
                 14 
                 3 
                 1/4 
                 1.8 ± 1.8 *** 
                 92.3 ± 27.7 * 
                 2.5 ± 2.5 *** 
                 86.2 
               
               
                   
               
               
                 * P &lt; 0.05, 
               
               
                 ** P &lt; 0.01, 
               
               
                 *** P &lt; 0.001 vs Vehicle. 
               
               
                 Each value represents the mean ± SE. 
               
               
                   a The cumulative total counts of vomiting response. 
               
               
                   b The latency of dog that did not show emetic response was considered as 120 min. 
               
               
                   c The cumulative total duration of vomiting response and the duration of dog that show once emetic response was considered as 0.5 min. 
               
               
                   d 0.09 w/v % Polysorbate 80/10% DMSO/saline 1 mL/kg, s.c. 
               
            
           
         
       
     
     Table 8 shows the effect of Compound 25, Compound 48, Compound 58, and Compound 260 on PYY (T-481, 10 μg/kg, s.c.) induced vomiting in dogs. The results are also shown in  FIG. 3 . 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Effect of Test Peptides on T-481 (10 μg/kg, s.c.)-induced vomiting in dogs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Doses 
                 No. of 
                 Emesis 
                   
                   
               
               
                 T-481 was 
                 Compound 
                 (nmol/kg, 
                 animals 
                 response a   
                 Latency b   
                 Duration c   
               
               
                 administered 
                 No. 
                 s.c.) 
                 (responder/used) 
                 (counts) 
                 (min) 
                 (min) 
               
               
                   
               
               
                 1 h after 
                 Vehicle d   
                 — 
                 4/4 
                 8.0 ± 1.9    
                 5.0 ± 0.9     
                 55.7 ± 22.4   
               
               
                   
                 25 
                 3 
                 0/4 
                 0.0 ± 0.0 *** 
                 120.0 ± 0.0 *** 
                 0.0 ± 0.0 ** 
               
               
                   
                 48 
                 3 
                 1/4 
                 0.3 ± 0.3 *** 
                 91.6 ± 28.4 * 
                 0.1 ± 0.1 ** 
               
               
                   
                 58 
                 3 
                 2/4 
                 0.5 ± 0.3 *** 
                 81.7 ± 25.8 * 
                 0.3 ± 0.1 ** 
               
               
                   
                 260  
                 3 
                 2/4 
                 0.5 ± 0.3 *** 
                 65.6 ± 31.4     
                 0.3 ± 0.1 ** 
               
               
                   
               
               
                 * P &lt; 0.05, 
               
               
                 ** P &lt; 0.01, 
               
               
                 *** P &lt; 0.001 vs Vehicle. 
               
               
                 Each value represents the mean ± SE. 
               
               
                   a The cumulative total counts of vomiting response. 
               
               
                   b The latency of dog that did not show emetic response was considered as 120 min. 
               
               
                   c The cumulative total duration of vomiting response and the duration of dog that show once emetic response was considered as 0.5 min. 
               
               
                   d 0.09 w/v % Polysorbate 80/10% DMSO/saline 1 mL/kg, s.c. 
               
            
           
         
       
     
     As shown in Table 7 and Table 8, it is verified that the compounds of the present invention inhibited PYY (T-481) induced emesis, including symptoms of vomiting. 
     Example 11: Y2R Agonist-Induced Emesis in Dogs 
     To evaluate the Y2R agonist-induced emesis in dogs, test compounds or vehicle (0.09% [w/v] Tween 80/10% DMSO/PBS) was administered subcutaneously (sc) to female beagle dogs (11 months old), followed by sc injections with Y2R agonist (T-3127481, 10 μg/kg) at 8 and 72 hours postdose. Emetic episodes were counted for 2 hours after each Y2R agonist administration (by blinded analysis). 
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                 No. of 
                   
                   
                   
               
               
                   
                   
                   
                   
                 No. of 
                 emetic 
                 Latency 
               
               
                 Day 
                   
                   
                   
                 animals that 
                 episodes 
                 period of 
                 Duration 
               
               
                 [after 
                 Cmpd. 
                 Dose 
                   
                 did not 
                 [% 
                 emesis 
                 of emesis 
                 PK  b)   
               
               
                 dosing] 
                 No. 
                 (nmol/kg) 
                 N 
                 vomit 
                 Inhibition  a) ] 
                 (min) 
                 (min) 
                 (nmol/L) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 Vehicle 
                 0 
                 4 
                 0 
                 6.5 ± 0.6 
                 6.3 ± 0.5 
                 43.8 ± 35.3 
                 ND 
               
               
                 [1 hr] 
                 142 
                 3 
                 4 
                 3 
                  0.5 ± 1.0** 
                     93.0 ± 54.0 #   
                 0.3 ± 0.5 
                 3.8 ± 1.4 
               
               
                   
                   
                   
                   
                   
                 [92.3%] 
               
               
                   
                  25 
                 0.3 
                 4 
                 0 
                     2.8 ± 2.1 #   
                 11.5 ± 3.1 #    
                 6.0 ± 8.5 
                 0.47 ± 0.03 
               
               
                   
                   
                   
                   
                   
                 [57.7%] 
               
               
                   
                 143 
                 3 
                 4 
                 1 
                 4.3 ± 5.9 
                 39.5 ± 53.8 
                  8.8 ± 16.2 
                 2.4 ± 0.9 
               
               
                   
                   
                   
                   
                   
                 [34.6%] 
               
               
                 4 
                 Vehicle 
                 0 
                 4 
                 0 
                 5.5 ± 1.3 
                 6.0 ± 1.2 
                 40.3 ± 33.5 
                 ND 
               
               
                 [72 hr] 
                 142 
                 3 
                 4 
                 0 
                 3.8 ± 2.5 
                 7.8 ± 2.8 
                 7.3 ± 7.1 
                 0 ± 0 
               
               
                   
                   
                   
                   
                   
                 [31.8%] 
               
               
                   
                  25 
                 0.3 
                 4 
                 0 
                 8.3 ± 2.6 
                 7.3 ± 3.0 
                 56.3 ± 24.0 
                 0 ± 0 
               
               
                   
                   
                   
                   
                   
                 [−50%] 
               
               
                   
                 143 
                 3 
                 4 
                 1 
                  1.8 ± 1.7* 
                 37.5 ± 55.0 
                  7.5 ± 14.3 
                 2.6 ± 2.1 
               
               
                   
                   
                   
                   
                   
                 [68.2%] 
               
               
                   
               
               
                 Significantly different from the vehicle group; 
               
               
                 *p ≤ 0.05, 
               
               
                 **p ≤ 0.01 (Student&#39;s t test), 
               
               
                   # p ≤ 0.05, 
               
               
                   ## p ≤ 0.01 (Aspin &amp; Welch t test), 
               
               
                 Data is expressed as mean ± S.D., 
               
               
                 ND: Not determined 
               
               
                   a)  Decreased ratio of the mean emetic episodes compared to those in the vehicle group 
               
               
                   b)  Plasma test article concentration at 8 and 72 hours after dosing of Compound 142, Compound 25, and Compound 143 (immediately before Y2R agonist administration). 
               
            
           
         
       
     
     As shown in Table 9, it is verified that the compounds of the present invention inhibited Y2R agonist-induced emesis, including symptoms of vomiting. 
     Example 12: Vomiting Suppression Test in Ferrets 
     1. Effect of subcutaneously administered GIP receptor agonist peptide in morphine-induced acute emetic model. 
     To evaluate the antiemetic effect, the GIP receptor agonist peptides compounds 25, 14, 142, 48, 17 and 20 other than natural human GIP are subcutaneously administered into male ferrets 30 minutes before morphine administration. Up to 60 minutes after morphine administration, the condition of the ferrets is monitored to record the frequencies and time points of abdominal contraction motions, vomiting behaviors, licking with the tongue, and fidgety behavior occurring. 
     GIP receptor agonist peptide compounds of the present disclosure are dosed at 0.1-10 nmol/kg to attenuate the morphine (0.6 mg/kg, s.c.)-induced emesis in the ferrets. 
     GIP receptor agonist peptides are dissolved with a vehicle (0.09 w/v % tween 80/10% DMSO/saline), respectively, to prepare test solutions. 0.5 mg/kg of the test solutions and the vehicle are subcutaneously administered to ferrets (4 in each group), respectively. At the time of each of 4 hours, after administration, 0.6 mg/kg of morphine is subcutaneously administered. Up to 60 minutes after morphine administration, the condition of the ferrets is monitored to record the number of animals that did not vomit, the number of emetic episodes, the latency period in minutes to observe the emetic episodes, the duration of the observed emesis if any. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Percent inhibition of emetic symptoms induced by morphine in ferrets 
               
               
                 treated with GIPr agonist peptides of the present disclosure. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 % inhibition of emetic events at 
               
               
                   
                 Compound 
                 SEQ 
                 doses (nmol/kg) shown in ferret 
               
               
                   
                 No. 
                 ID No. 
                 morphine model 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 25 
                 26 
                 54% (0.1 nmol/kg); 
               
               
                   
                   
                   
                 100% (0.3 nmol/kg); 
               
               
                   
                   
                   
                 100% (1 nmol/kg) 
               
               
                   
                 14 
                 15 
                 87% (1 nmol/kg); 
               
               
                   
                   
                   
                 100% (3 nmol/kg); 
               
               
                   
                   
                   
                 100% (10 nmol/kg) 
               
               
                   
                 142 
                 143 
                 71% (0.3 nmol/kg) 
               
               
                   
                 48 
                 49 
                 75% (0.3 nmol/kg) 
               
               
                   
                 17 
                 18 
                 100% (3 nmol/kg) 
               
               
                   
                 20 
                 21 
                 83% (3 nmol/kg) 
               
               
                   
                   
               
            
           
         
       
     
     Results from the above example, clearly illustrate that multiple GIPr agonist peptides 25, 14, 142, 48, 17 and 20 were effective in strongly suppressing emesis induced by morphine in ferrets. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Effect of Compound 25 on morphine (0.6 mg/kg, s.c.)-induced emesis in ferrets 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Morphine 
                   
                   
                 Doses 
                 No. of 
                   
                   
                   
               
               
                 was 
                   
                 Compound 
                 (nmol/kg, 
                 animals 
                 Latency a   
                 Duration b   
               
               
                 administered 
                 Signs 
                 No. 
                 s.c.) 
                 (responder/used) 
                 (min) 
                 (min) 
                 Frequency 
               
               
                   
               
               
                 4 h after 
                 Retching 
                 Vehicle c   
                 — 
                 4/4 
                 1.8 ± 1.0 
                 10.5 ± 5.6  
                 37.8 ± 20.1 
               
               
                   
                   
                 25 
                 0.1 
                 2/4 
                 16.5 ± 15.6 
                 3.5 ± 4.7  
                 17.3 ± 20.0 
               
               
                   
                   
                   
                 0.3 
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                   
                   
                 1   
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                 Vomiting 
                 Vehicle c   
                 — 
                 4/4 
                 1.8 ± 1.0 
                 3.8 ± 2.1  
                 4.8 ± 3.9 
               
               
                   
                   
                 25 
                 0.1 
                 2/4 
                 16.5 ± 15.6 
                 2.8 ± 4.9  
                 2.3 ± 3.9 
               
               
                   
                   
                   
                 0.3 
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                   
                   
                 1   
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                 Emesis 
                 Vehicle c   
                 — 
                 4/4 
                 1.8 ± 1.0 
                 10.8 ± 5.3  
                 42.5 ± 24.0 
               
               
                   
                   
                 25 
                 0.1 
                 2/4 
                 16.5 ± 15.6 
                 3.5 ± 4.7* 
                 19.5 ± 22.9 
               
               
                   
                   
                   
                 0.3 
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                   
                   
                 1   
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                 Licking 
                 Vehicle c   
                 — 
                 3/4 
                  9.8 ± 13.7 
                 2.5 ± 2.4  
                 2.5 ± 2.4 
               
               
                   
                   
                 25 
                 0.1 
                 2/4 
                 16.8 ± 15.3 
                 1.0 ± 1.4  
                 1.0 ± 1.4 
               
               
                   
                   
                   
                 0.3 
                 0/4 
                 30.0 ± 0.0* 
                 0.0 ± 0.0  
                 0.0 ± 0.0 
               
               
                   
                   
                   
                 1   
                 0/4 
                 30.0 ± 0.0* 
                 0.0 ± 0.0  
                 0.0 ± 0.0 
               
               
                   
                 Fidget 
                 Vehicle c   
                 — 
                 4/4 
                 1.8 ± 1.0 
                 10.3 ± 5.9  
                 4.3 ± 2.6 
               
               
                   
                   
                 25 
                 0.1 
                 2/4 
                 16.5 ± 15.6 
                 2.5 ± 4.4* 
                  1.3 ± 1.5* 
               
               
                   
                   
                   
                 0.3 
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
                   
                   
                 1   
                  0/4# 
                  30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0* 
               
               
                   
               
               
                 Each value represents the mean ± S.D. 
               
               
                   a The latency of ferret that did not show emetic response was considered as 30 min. 
               
               
                   b The cumulative total duration of emetic response. 
               
               
                   c 0.09 w/v % Polysorbate 80/10% DMSO/PBS 0.5 mL/kg, s.c. 
               
               
                   # Significant difference from vehicle treatment p &lt; 0.05 (Fisher&#39;s exact test) 
               
               
                 * and **Significant difference from vehicle treatment p &lt; 0.05 and p &lt; 0.01, respectively (Student&#39;s t-test or Aspin-Welch&#39;s t-test, One-side) 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Effect of Compound 14 on morphine (0.6 mg/kg, s.c.)-induced emesis in ferrets 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 No. of 
                   
                   
                   
               
               
                 Morphine 
                   
                   
                 Doses 
                 animals 
               
               
                 was 
                   
                 Compound 
                 (nmol/kg, 
                 (responder/ 
                 Latency a   
                 Duration b   
               
               
                 administered 
                 Signs 
                 No. 
                 s.c.) 
                 used) 
                 (min) 
                 (min) 
                 Frequency 
               
               
                   
               
               
                 4 h after 
                 Retching 
                 Vehicle c   
                 — 
                 4/4  
                 4.0 ± 0.8  
                 9.3 ± 5.9  
                 26.8 ± 11.4  
               
               
                   
                   
                 14 
                 1 
                 1/4  
                 23.8 ± 12.5* 
                 0.3 ± 0.5* 
                  3.5 ± 7.0** 
               
               
                   
                   
                   
                 3 
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0** 
               
               
                   
                   
                   
                 10  
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0 0 ± 0.0** 
               
               
                   
                 Vomiting 
                 Vehicle c   
                 — 
                 4/4  
                 5.5 ± 2.1  
                 8.3 ± 5.0  
                 3.5 ± 1.7  
               
               
                   
                   
                 14 
                 1 
                 1/4  
                 24.0 ± 12.0* 
                 0.3 ± 0.5* 
                  0.3 ± 0.5** 
               
               
                   
                   
                   
                 3 
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
                   
                   
                 10  
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
                 Emesis 
                 Vehicle c   
                 — 
                 4/4  
                 4.0 ± 0.8  
                 9.8 ± 6.3  
                 30.3 ± 13.1  
               
               
                   
                   
                 14 
                 1 
                 1/4  
                 23.8 ± 12.5* 
                 0.3 ± 0.5* 
                  3.8 ± 7.8** 
               
               
                   
                   
                   
                 3 
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0** 
               
               
                   
                   
                   
                 10  
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                  0.0 ± 0.0** 
               
               
                   
                 Licking 
                 Vehicle c   
                 — 
                 4/4  
                 4.0 ± 0.8  
                 8.3 ± 6.6  
                 4.5 ± 3.7  
               
               
                   
                   
                 14 
                 1 
                 1/4  
                 23.8 ± 12.5* 
                 0.3 ± 0.5* 
                 0.3 ± 0.5  
               
               
                   
                   
                   
                 3 
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
                   
                   
                 10  
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
                 Fidget 
                 Vehicle c   
                 — 
                 4/4  
                 4.0 ± 0.8  
                 9.3 ± 5.9  
                 4.5 ± 2.6  
               
               
                   
                   
                 14 
                 1 
                 1/4  
                 23.8 ± 12.5* 
                 0.3 ± 0.5* 
                 0.5 ± 1.0* 
               
               
                   
                   
                   
                 3 
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
                   
                   
                 10  
                 0/4# 
                 30.0 ± 0.0** 
                 0.0 ± 0.0* 
                 0.0 ± 0.0* 
               
               
                   
               
               
                 Each value represents the mean ± S.D. 
               
               
                   a The latency of ferret that did not show emetic response was considered as 30 min. 
               
               
                   b The cumulative total duration of emetic response. 
               
               
                   c 0.09 w/v % Polysorbate 80/10% DMSO/PBS 0.5 mL/kg, s.c. 
               
               
                 #Significant difference from vehicle treatment p &lt; 0.05 (.Fisher&#39;s exact test) 
               
               
                 * and **Significant difference frost vehicle treatment p &lt; 0.05 and p &lt; 0.01, respectively (Student&#39;s t-test or Aspin-Welch&#39;s t-test, One-side) 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Effect of Compound 142 and Compound 48 on morphine (0.6 mg/kg, s.c.)-induced emesis in ferrets 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 No. of 
                   
                   
                   
               
               
                 Morphine 
                   
                   
                 Doses 
                 animals 
               
               
                 was 
                   
                 Compound 
                 (nmol/kg, 
                 (responder/ 
                 Latency a   
                 Duration b   
               
               
                 administered 
                 Signs 
                 No. 
                 s.c.) 
                 used) 
                 (min) 
                 (min) 
                 Frequency 
               
               
                   
               
               
                 4 h after 
                 Retching 
                 Vehicle c   
                 — 
                 4/4 
                 4.3 ± 2.6  
                 9.8 ± 3.1  
                 28.8 ± 9.9   
               
               
                   
                   
                 142  
                 0.3 
                 3/4 
                 9.8 ± 13.6 
                 1.5 ± 1.7** 
                 9.0 ± 11.7* 
               
               
                   
                   
                 48 
                 0.1 
                 4/4 
                 3.5 ± 0.6  
                 2.3 ± 2.5** 
                 8.3 ± 5.1** 
               
               
                   
                   
                 48 
                 0.3 
                 1/4 
                 23.3 ± 13.5* 
                 0.8 ± 1.5** 
                 7.5 ± 15.0* 
               
               
                   
                 Vomiting 
                 Vehicle c   
                 — 
                 4/4 
                 5.3 ± 4.6  
                 8.5 ± 2.4  
                 4.5 ± 2.1  
               
               
                   
                   
                 142  
                 0.3 
                 1/4 
                 23.0 ± 14.0* 
                 1.0 ± 2.0** 
                 0.5 ± 1.0** 
               
               
                   
                   
                 48 
                 0.1 
                 2/4 
                 16.8 ± 15.3  
                 0.5 ± 0.6** 
                 0.5 ± 0.6** 
               
               
                   
                   
                 48 
                 0.3 
                 1/4 
                 23.3 ± 13.5* 
                 0.8 ± 1.5** 
                 0.8 ± 1.5*  
               
               
                   
                 Emesis 
                 Vehicle c   
                 — 
                 4/4 
                 4.3 ± 2.6  
                 10.0 ± 3.2   
                 33.3 ± 8.2   
               
               
                   
                   
                 142  
                 0.3 
                 3/4 
                 9.8 ± 13.6 
                 1.5 ± 1.7** 
                  9.5 ± 12.7** 
               
               
                   
                   
                 48 
                 0.1 
                 4/4 
                 3.5 ± 0.6  
                 2.3 ± 2.5** 
                 8.8 ± 5.6** 
               
               
                   
                   
                 48 
                 0.3 
                 1/4 
                 23.3 ± 13.5* 
                 0.8 ± 1.5** 
                 8.3 ± 16.5* 
               
               
                   
                 Licking 
                 Vehicle c   
                 — 
                 4/4 
                 6.5 ± 3.0  
                 5.3 ± 5.3  
                 3.8 ± 3.4  
               
               
                   
                   
                 142  
                 0.3 
                 1/4 
                 24.0 ± 12.0* 
                 0.3 ± 0.5  
                 0.3 ± 0.5  
               
               
                   
                   
                 48 
                 0.1 
                 1/4 
                  24.8 ± 10.5** 
                 0.3 ± 0.5  
                 0.3 ± 0.5  
               
               
                   
                   
                 48 
                 0.3 
                 1/4 
                 24.0 ± 12.0* 
                 0.3 ± 0.5  
                 0.3 ± 0.5  
               
               
                   
                 Fidget 
                 Vehicle c   
                 — 
                 4/4 
                 4.5 ± 2.4  
                 6.5 ± 2.9  
                 3.3 ± 1.3  
               
               
                   
                   
                 142  
                 0.3 
                 3/4 
                 9.8 ± 13.6 
                 1.5 ± 1.7*  
                 1.3 ± 1.3*  
               
               
                   
                   
                 48 
                 0.1 
                 4/4 
                 3.5 ± 0.6  
                 1.3 ± 0.5*  
                 1.5 ± 0.6*  
               
               
                   
                   
                 48 
                 0.3 
                 1/4 
                 23.3 ± 13.5* 
                 0.8 ± 1.5** 
                 0.5 ± 1.0** 
               
               
                   
               
               
                 Each value represents the mean ± S.D. 
               
               
                   a The latency of ferret that did not show emetic response was considered as 30 min. 
               
               
                   b The cumulative total duration of emetic response. 
               
               
                   c 0.09 w/v % Polysorbate 80/10% DMSO/PBS 0.5 mL/kg, s.c. 
               
               
                 No Significant difference from vehicle treatment (Fisher&#39;s exact test) 
               
               
                 * and **Significant difference from vehicle treatment p &lt; 0.05 and p &lt; 0.01, respectively (Student&#39;s t-test or Aspin-Welch&#39;s t-test, One-side) 
               
            
           
         
       
     
     Results from the above morphine induced emesis example, clearly illustrate that Compounds 14 (SEQ ID NO: 15), Compound 48 (SEQ ID NO:), Compound 25 (SEQ ID NO: 26), and Compound 142 (SEQ ID NO: 143) are effective in inhibiting the frequency of emetic events, including frequency of both retching and vomiting events in ferrets dosed with morphine. 
     Example 13: Apomorphine Induced Emesis in Dog 
     Dogs are transferred to an observation cage (700 mm W×700 mm D×700 mm H [W×D×H], without food) on 1 day before each apomorphine challenge. The dogs are weighed by using an electronic balance then test articles will be administrated via the subcutaneous route. Apomorphine is challenged at 8 hr after the administration and emetic events will be monitored for 1 h by video recording. The second apomorphine challenge will be 72 hr after the administration and emetic events will be recorded by the same protocol. Emesis symptoms are continuously recorded using a video camera and stored on a blue ray disc. Observations of symptoms include retching (a rhythmic contraction of the abdomen) and vomiting (vomiting behavior, including the elimination of vomitus or similar behavior). Besides, the combination of retching and vomiting is defined as emesis, and the number of episodes, latency (time elapsed from morphine administration until the onset of the first emesis symptom), duration (time elapsed between the onset of the first and final episodes of emesis), and frequency (number of animals showing emesis/number of experimental animals) of each of these symptoms is calculated. The latency in cases where emesis symptoms are not noted is taken as the maximum value (1 h for apomorphine challenge) at the end of observation. When the duration of the emesis symptoms is less than 1 min, the duration is recorded, for convenience, as 1 min. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 shows the results of the apomorphine testing: 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 % inhibition of emetic events at 
               
               
                   
                   
                   
                 doses (nmol/kg) shown in dog 
               
               
                   
                 Compound 
                 Sequence 
                 Apomorphine model after 8 hrs 
               
               
                   
                 No. 
                 ID No. 
                 (or *72 hours) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 14 
                 15 
                 92% (30 nmol/kg) 
               
               
                   
                 17 
                 18 
                 92% (30 nmol/kg); 
               
               
                   
                   
                   
                 68% (10 nmol/kg) 
               
               
                   
                 20 
                 21 
                 69% (30 nmol/kg) 
               
               
                   
                 21 
                 22 
                 71% (10 nmol/kg) 
               
               
                   
                 25 
                 26 
                 78% (30 nmol/kg); 
               
               
                   
                   
                   
                 70% (10 nmol/kg); 
               
               
                   
                   
                   
                 39% (3 nmol/kg) 
               
               
                   
                 48 
                 49 
                 71% (10 nmol/kg); 
               
               
                   
                   
                   
                 38% (3 nmol/kg) 
               
               
                   
                 140 
                 141 
                 76% (10 nmol/kg) 
               
               
                   
                 141 
                 142 
                 52% (10 nmol/kg) 
               
               
                   
                 142 
                 143 
                 76% (10 nmol/kg); 
               
               
                   
                   
                   
                 77% (30 nmol/kg); 
               
               
                   
                   
                   
                 54% (3 nmol/kg) 
               
               
                   
                 148 
                 149 
                 55% (30 nmol/kg), 
               
               
                   
                   
                   
                 69% (60nmol/kg*) 
               
               
                   
                   
               
            
           
         
       
     
     Results from the above example, clearly illustrate that Compounds 14, 17, 20, 21, 25, 48, 140, 142 and 148 are effective in inhibiting the frequency of emetic events in ferrets dosed with morphine in a dose dependent manner. 
     Example 14: Serum Half-Life and Percentage Remaining at 48 Hours 
     Serum Half-Life Analysis 
     Human plasma (mixed gender: sodium heparin is used as anti-coagulant; pre-adjusted to pH 7.4—NB alternative species may be used) is spiked with each test peptide (500 nM) and incubated ·cn=3) at 37° C. for 48 hours in a 5% CO2 environment. Aliquots are taken at 0. 1, 2, 4, 7, 24 and 46 hours and pH adjusted to pH 3 with 20% formic acid prior to analysis. Appropriate positive control compounds will be incubated in parallel, in addition to a no plasma control, sampled at 0 and 8 hours. All samples will be treated with ice-cold acetonitrile/methanol (4:1 (v/v)) containing internal standard prior to centrifugation at 2000 g and 4° C. for 10 minutes and subjected to LC-MS/MS analysis. 
     Sample Analysis 
     The samples are analyzed by LC-MS/MS using a 6500 (or equivalent) triple quadrupole mass spectrometer (AB Sciex) coupled to an appropriate Liquid Chromatography (LC) system. Protein binding and stability values are determined via peak area ratios using multiple reaction monitoring (MRM) parameters following compound optimisation. Multiple reaction monitoring (MRM) is a highly sensitive method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides based on the screening of specified precursor peptide-to-fragment ion transitions. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 shows the results of the Serum half-life of the compounds 
               
               
                 and the percentage remaining at 48 hours: 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 Sequence 
                 Serum t 1/2   
                 % Remaining 
               
               
                   
                 No. 
                 ID No. 
                 (hours) 
                 at 48 hr 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 5 
                 6 
                 0.6 
                 0 
               
               
                   
                 11 
                 12 
                 1.99 
                 0 
               
               
                   
                 12 
                 13 
                 0.97 
                 0 
               
               
                   
                 16 
                 17 
                 &gt;48 
                 107.1 
               
               
                   
                 17 
                 18 
                 &gt;48 
                 116 
               
               
                   
                 18 
                 19 
                 &gt;48 
                 145.3 
               
               
                   
                 19 
                 20 
                 &gt;48 
                 131.5 
               
               
                   
                 20 
                 21 
                 &gt;48 
                 122 
               
               
                   
                 21 
                 22 
                 &gt;48 
                 116.5 
               
               
                   
                 22 
                 23 
                 11.82 
                 5.6 
               
               
                   
                 23 
                 24 
                 13.33 
                 6.5 
               
               
                   
                 24 
                 25 
                 16.31 
                 12.1 
               
               
                   
                 25 
                 26 
                 18.14 
                 14.2 
               
               
                   
                 26 
                 27 
                 0.67 
                 0 
               
               
                   
                 27 
                 28 
                 1.13 
                 0 
               
               
                   
                 28 
                 29 
                 37.88 
                 41.5 
               
               
                   
                 29 
                 30 
                 30.65 
                 34.1 
               
               
                   
                 30 
                 31 
                 13.49 
                 8 
               
               
                   
                 31 
                 32 
                 16.84 
                 12.5 
               
               
                   
                   
               
            
           
         
       
     
     Table 15 provides two data points related to the pharmacokinetic activity of the GIPR agonist peptides of the present disclosure. Optimum values for the use of the GIPR agonist peptides of the present disclosure range between a serum T½ (half life) of 10-20 hours for once daily dosing. As can be seen from Table 15, when the T½ in serum approaches 30 hours and greater, the amount remaining after 48 hours exceeds 30%, which indicates that the peptide is accumulating and not being made available to exert its pharmacological activity. 
     Example 15: Human Plasma Protein Binding (PPB) 
     Stock Solutions 
     Stock solutions: (1000 μM) of the peptides are prepared in DMSO. 
     Plasma Protein Binding (PPB) Analysis 
     Human plasma (mixed gender; containing K2-EDTA as anti-coagulant; pre-adjusted to pH 7.4—NB alternative species may be used) is spiked individually with each test peptide (1000 nmol/L), sampled for analysis and then incubated (n=4) at 37° C. in a water bath for 30 minutes. Following the incubation period, the plasma is sampled for analysis, then transferred to ultracentrifugation tubes and centrifuged (n=3) at −450,000 g and 4° C. for 3 hours, after which the supernatant is sampled for analysis. An additional aliquot of the supernatant is taken at the end of the centrifugation period to determine the total protein concentration. An aliquot of the incubated plasma will be stored at 4° C. for 3 hours and then sampled for analysis. At the point of sampling, all samples are matrix-matched, treated with ice-cold acetonitrile/methanol (4:1 (vfv)) containing internal standard, centrifuged al 2000 g and 4° C. for 10 minutes and stored prior to LC-MS/MS analysis. An appropriate positive control compound control will be incubated and centrifuged in parallel; control plasma is also centrifuged to generate samples for matrix-matching. Fraction unbound (Fu) values is determined by comparison of the analyte response in plasma to the analyte response in the supernatant, determined via peak area response ratios. 
     Plasma Stability Analysis 
     Human plasma (mixed gender: sodium heparin is used as anti-coagulant; pre-adjusted to pH 7.4—NB alternative species may be used) is spiked with each test peptide (500 nM) and incubated ·cn=3) at 37° C. for 48 hours in a 5% CO2 environment. Aliquots are taken at 0. 1, 2, 4, 7, 24 and 46 hours and pH adjusted to pH 3 with 20% formic acid prior to analysis. Appropriate positive control compounds will be incubated in parallel, in addition to a no plasma control, sampled at 0 and 8 hours. All samples will be treated with ice-cold acetonitrile/methanol (4:1 (v/v)) containing internal standard prior to centrifugation at 2000 g and 4° C. for 10 minutes and subjected to LC-MS/MS analysis. 
     Sample Analysis 
     The samples are analyzed by LC-MS/MS using a 6500 (or equivalent) triple quadrupole mass spectrometer (AB Sciex) coupled to an appropriate Liquid Chromatography (LC) system. Protein binding and stability values are determined via peak area ratios using multiple reaction monitoring (MRM) parameters following compound optimisation. Multiple reaction monitoring (MRM) is a highly sensitive method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides based on the screening of specified precursor peptide-to-fragment ion transitions. 
     Dog PPB values presented below are obtained essentially as described for Human PPB samples, with the difference being that dog serum is used instead of human serum. Table 16 is provided with the values of (Fu, plasma) as fraction unbound expressed as a percentage compared to the percent bound. i.e. if the value is 0.0123, then the fraction unbound is (0.0123/100)%, which is 1.23% of the peptide is unbound and 98.77% is bound in plasma. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 shows the results of the dog PPB and Human PPB: 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 SEQ 
                 Human PPB 
                 Dog PPB 
               
               
                   
                 No. 
                 ID No. 
                 (Fu, plasma ) 
                 (Fu, plasma ) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 14 
                 15 
                 0.0533 
                 0.0439 
               
               
                   
                 16 
                 17 
                 0.0441 
                 0.0151 
               
               
                   
                 17 
                 18 
                 0.064 
                 0.0675 
               
               
                   
                 18 
                 19 
                 0.0588 
                 0.0517 
               
               
                   
                 19 
                 20 
                 0.0321 
                 0.0361 
               
               
                   
                 20 
                 21 
                 0.0013 
                 0.0021 
               
               
                   
                 21 
                 22 
                 0.0414 
                 0.037 
               
               
                   
                 22 
                 23 
                 0.0413 
               
               
                   
                 23 
                 24 
                 0.0734 
               
               
                   
                 24 
                 25 
                 0.0512 
               
               
                   
                 25 
                 26 
                 0.0459 
                 0.0401 
               
               
                   
                 29 
                 30 
                 0.018 
               
               
                   
                 30 
                 31 
                 0.0407 
               
               
                   
                 119 
                 120 
                 0.0185 
                 0.0105 
               
               
                   
                 142 
                 143 
                 0.0111 
                 0.003 
               
               
                   
                   
               
            
           
         
       
     
     As can be seen in Table 16, the GIPR agonist peptides of the present disclosure provide a percent of unbound or active drug for antiemetic activity, which ranges from about 0.1% to about 7.3%. The efficacy of the GIPR agonist peptide will be related to the exposure to the amount of unbound drug in plasma, i.e. the proportion free peptide to penetrate into surrounding tissues. The bound peptide in plasma can also serve as a reservoir for free peptide removed by various elimination processes thus prolonging the duration of action. These GIPR agonist peptides also demonstrate that due to the high proportion of the drug being bound (98.9% to 92.7%), the duration of action can be extended for longer periods of time. GIPR agonist peptides of the present disclosure provide an optimum range of unbound to plasma protein for once daily dosing to human subjects between 1-5% unbound. It is believed that GIPR agonist peptides of the present disclosure having a free fraction of about 1% to about 5% translates to a peptide having a desirable pK profile, demonstrating fast absorption and fast elimination to prevent excessive accumulation. Several compounds in Table 16 demonstrate optimum free unbound peptide, for example, compounds 14, 16, 18, 19, 21, 22, 24, 25, and 30. 
     Example 16: Solubility of the GIPR Agonist Compounds 
     3 mg of peptides are weighted out in a small glass vial. 100 uL of 200 mM Phosphate buffer pH 7.4 are added and the vial is sonicated/vortexed as necessary for a maximum of 1 min. A visual inspection is performed, If the sample is fully dissolved, the solubility is recorded as 30 mg/mL. If insoluble material is observed in the tube the addition of 100 uL of buffer and mixing is repeated until complete dissolution. If the peptide is not soluble in 500 uL of buffer, it is labeled as solubility &lt;6 mg/mL. The solubility can be confirmed by RP-HPLC after filtration on 0.2 μm filter on an Agilent 1200 system with a Kinetex column form Phenomenex® (2.6 μm EVO C18 100 Å, LC Column 50×3.0 mm) kept at 40° C., the eluent A is 0.05% TFA in Water, B is 0.035% TFA in Acetonitrile at a 0.6 ml/min flow rate. The gradient was from 20 to 70 over 5 min, the column is then washed for 1 min at 90% B. UV monitoring at 215 nm was used to monitor peptide concentration. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 shows the results of the solubility of the 
               
               
                 compounds in phosphate buffer at pH 7.4: 
               
            
           
           
               
               
               
            
               
                   
                   
                 pH 7.4 Phosphate 
               
               
                 Compound 
                 SEQ 
                 Buffer - Solubility 
               
               
                 No. 
                 ID No. 
                 (mg/mL) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 2 
                 15 
               
               
                 2 
                 3 
                 15 
               
               
                 3 
                 4 
                 15 
               
               
                 4 
                 5 
                 15 
               
               
                 5 
                 6 
                 15 
               
               
                 6 
                 7 
                 15 
               
               
                 7 
                 8 
                 15 
               
               
                 8 
                 9 
                 15 
               
               
                 9 
                 10 
                 15 
               
               
                 10 
                 11 
                 15 
               
               
                 11 
                 12 
                 15 
               
               
                 12 
                 13 
                 15 
               
               
                 13 
                 14 
                 30 
               
               
                 14 
                 15 
                 15 
               
               
                 15 
                 16 
                 30 
               
               
                 16 
                 17 
                 30 
               
               
                 17 
                 18 
                 30 
               
               
                 18 
                 19 
                 30 
               
               
                 19 
                 20 
                 30 
               
               
                 20 
                 21 
                 30 
               
               
                 21 
                 22 
                 30 
               
               
                 22 
                 23 
                 30 
               
               
                 23 
                 24 
                 30 
               
               
                 24 
                 25 
                 30 
               
               
                 25 
                 26 
                 30 
               
               
                 26 
                 27 
                 30 
               
               
                 27 
                 28 
                 30 
               
               
                 28 
                 29 
                 30 
               
               
                 29 
                 30 
                 30 
               
               
                 30 
                 31 
                 30 
               
               
                 31 
                 32 
                 30 
               
               
                 32 
                 33 
                 30 
               
               
                 33 
                 34 
                 30 
               
               
                 34 
                 35 
                 30 
               
               
                 35 
                 36 
                 30 
               
               
                 36 
                 37 
                 30 
               
               
                 37 
                 38 
                 15 
               
               
                 38 
                 39 
                 30 
               
               
                 39 
                 40 
                 30 
               
               
                 40 
                 41 
                 30 
               
               
                 41 
                 42 
                 30 
               
               
                 42 
                 43 
                 30 
               
               
                 43 
                 44 
                 30 
               
               
                 44 
                 45 
                 30 
               
               
                 45 
                 46 
                 30 
               
               
                 46 
                 47 
                 30 
               
               
                 47 
                 48 
                 30 
               
               
                 48 
                 49 
                 30 
               
               
                 49 
                 50 
                 30 
               
               
                 50 
                 51 
                 30 
               
               
                 51 
                 52 
                 30 
               
               
                 52 
                 53 
                 30 
               
               
                 53 
                 54 
                 30 
               
               
                 54 
                 55 
                 30 
               
               
                 55 
                 56 
                 30 
               
               
                 56 
                 57 
                 15 
               
               
                 57 
                 58 
                 15 
               
               
                 58 
                 59 
                 15 
               
               
                 59 
                 60 
                 15 
               
               
                 60 
                 61 
                 30 
               
               
                 61 
                 62 
                 30 
               
               
                 62 
                 63 
                 30 
               
               
                 63 
                 64 
                 15 
               
               
                 64 
                 65 
                 30 
               
               
                 65 
                 66 
                 15 
               
               
                 66 
                 67 
                 15 
               
               
                 67 
                 68 
                 15 
               
               
                 68 
                 69 
                 15 
               
               
                 69 
                 70 
                 15 
               
               
                 70 
                 71 
                 15 
               
               
                 71 
                 72 
                 15 
               
               
                 72 
                 73 
                 15 
               
               
                 73 
                 74 
                 30 
               
               
                 74 
                 75 
                 30 
               
               
                 75 
                 76 
                 15 
               
               
                 76 
                 77 
                 15 
               
               
                 77 
                 78 
                 30 
               
               
                 78 
                 79 
                 30 
               
               
                 79 
                 80 
                 15 
               
               
                 80 
                 81 
                 30 
               
               
                 81 
                 82 
                 30 
               
               
                 82 
                 83 
                 30 
               
               
                 83 
                 84 
                 30 
               
               
                 84 
                 85 
                 30 
               
               
                 85 
                 86 
                 30 
               
               
                 86 
                 87 
                 30 
               
               
                 87 
                 88 
                 30 
               
               
                 88 
                 89 
                 30 
               
               
                 89 
                 90 
                 15 
               
               
                 90 
                 91 
                 15 
               
               
                 91 
                 92 
                 15 
               
               
                 92 
                 93 
                 15 
               
               
                 93 
                 94 
                 30 
               
               
                 94 
                 95 
                 30 
               
               
                 95 
                 96 
                 30 
               
               
                 96 
                 97 
                 30 
               
               
                 97 
                 98 
                 30 
               
               
                 98 
                 99 
                 30 
               
               
                 99 
                 100 
                 30 
               
               
                 100 
                 101 
                 30 
               
               
                 101 
                 102 
                 30 
               
               
                 102 
                 103 
                 30 
               
               
                 103 
                 104 
                 30 
               
               
                 104 
                 105 
                 30 
               
               
                 105 
                 106 
                 30 
               
               
                 106 
                 107 
                 30 
               
               
                 107 
                 108 
                 30 
               
               
                 108 
                 109 
                 15 
               
               
                 109 
                 110 
                 30 
               
               
                 110 
                 111 
                 30 
               
               
                 111 
                 112 
                 30 
               
               
                 112 
                 113 
                 30 
               
               
                 113 
                 114 
                 30 
               
               
                 114 
                 115 
                 30 
               
               
                 115 
                 116 
                 15 
               
               
                 116 
                 117 
                 30 
               
               
                 117 
                 118 
                 30 
               
               
                 118 
                 119 
                 30 
               
               
                 119 
                 120 
                 30 
               
               
                 120 
                 121 
                 30 
               
               
                 121 
                 122 
                 30 
               
               
                 122 
                 123 
                 30 
               
               
                 123 
                 124 
                 30 
               
               
                 124 
                 125 
                 30 
               
               
                 125 
                 126 
                 30 
               
               
                 126 
                 127 
                 30 
               
               
                 127 
                 128 
                 30 
               
               
                 128 
                 129 
                 30 
               
               
                 129 
                 130 
                 30 
               
               
                 130 
                 131 
                 30 
               
               
                 131 
                 132 
                 30 
               
               
                 132 
                 133 
                 30 
               
               
                 133 
                 134 
                 30 
               
               
                 134 
                 135 
                 30 
               
               
                 135 
                 136 
                 30 
               
               
                 136 
                 137 
                 30 
               
               
                 137 
                 138 
                 30 
               
               
                 138 
                 139 
                 30 
               
               
                 139 
                 140 
                 30 
               
               
                 140 
                 141 
                 30 
               
               
                 141 
                 142 
                 30 
               
               
                 142 
                 143 
                 30 
               
               
                 143 
                 144 
                 30 
               
               
                 144 
                 145 
                 30 
               
               
                 145 
                 146 
                 30 
               
               
                 146 
                 147 
                 30 
               
               
                 147 
                 148 
                 30 
               
               
                 148 
                 149 
                 30 
               
               
                 149 
                 150 
                 30 
               
               
                 150 
                 151 
                 30 
               
               
                 151 
                 152 
                 30 
               
               
                 152 
                 153 
                 30 
               
               
                 153 
                 154 
                 30 
               
               
                 154 
                 155 
                 30 
               
               
                 155 
                 156 
                 30 
               
               
                 156 
                 157 
                 30 
               
               
                 157 
                 158 
                 30 
               
               
                 158 
                 159 
                 30 
               
               
                 159 
                 160 
                 30 
               
               
                 160 
                 161 
                 30 
               
               
                 161 
                 162 
                 30 
               
               
                 162 
                 163 
                 30 
               
               
                 163 
                 164 
                 30 
               
               
                 164 
                 165 
                 &lt;16 
               
               
                 165 
                 166 
                 30 
               
               
                 166 
                 167 
                 30 
               
               
                 167 
                 168 
                 30 
               
               
                 168 
                 169 
                 30 
               
               
                 169 
                 170 
                 30 
               
               
                 170 
                 171 
                 30 
               
               
                 171 
                 172 
                 30 
               
               
                 172 
                 173 
                 30 
               
               
                 173 
                 174 
                 30 
               
               
                 174 
                 175 
                 30 
               
               
                 175 
                 176 
                 30 
               
               
                 176 
                 177 
                 30 
               
               
                 177 
                 178 
                 30 
               
               
                 178 
                 179 
                 30 
               
               
                 179 
                 180 
                 30 
               
               
                 180 
                 181 
                 30 
               
               
                 181 
                 182 
                 30 
               
               
                 182 
                 183 
                 30 
               
               
                 183 
                 184 
                 30 
               
               
                 184 
                 185 
                 30 
               
               
                 185 
                 186 
                 30 
               
               
                 186 
                 187 
                 30 
               
               
                 187 
                 188 
                 60 
               
               
                 188 
                 189 
                 30 
               
               
                 189 
                 190 
                 30 
               
               
                 226 
                 227 
                 0.8 
               
               
                 227 
                 228 
                 0.7 
               
               
                 228 
                 229 
                 0.7 
               
               
                 229 
                 230 
                 7.7 
               
               
                 230 
                 231 
                 6.8 
               
               
                 231 
                 232 
                 0.7 
               
               
                 232 
                 233 
                 0.7 
               
               
                 233 
                 234 
                 7.1 
               
               
                 234 
                 235 
                 7 
               
               
                 235 
                 236 
                 0.8 
               
               
                 236 
                 237 
                 0.7 
               
               
                 237 
                 238 
                 0.8 
               
               
                 238 
                 239 
                 13.7 
               
               
                 239 
                 240 
                 6 
               
               
                 240 
                 241 
                 6 
               
               
                 241 
                 242 
                 0.9 
               
               
                 242 
                 243 
                 7.5 
               
               
                 243 
                 244 
                 10 
               
               
                 244 
                 245 
                 10 
               
               
                 245 
                 246 
                 7.5 
               
               
                 246 
                 247 
                 6 
               
               
                 247 
                 248 
                 10 
               
               
                 248 
                 249 
                 7.5 
               
               
                 249 
                 250 
                 7.5 
               
               
                 250 
                 251 
                 10 
               
               
                 251 
                 252 
                 &lt;6.00 
               
               
                 252 
                 253 
                 &lt;6.00 
               
               
                 253 
                 254 
                 10 
               
               
                 254 
                 255 
                 10 
               
               
                 255 
                 256 
                 &lt;6.00 
               
               
                 256 
                 257 
                 &lt;6.00 
               
               
                 257 
                 258 
                 6 
               
               
                 258 
                 259 
                 6 
               
               
                 259 
                 260 
                 &lt;6.00 
               
               
                 260 
                 261 
                 6 
               
               
                 261 
                 262 
                 6 
               
               
                 262 
                 263 
                 6 
               
               
                 263 
                 264 
                 6 
               
               
                 264 
                 265 
                 &lt;6.00 
               
               
                 265 
                 266 
                 6 
               
               
                 266 
                 267 
                 6 
               
               
                 267 
                 268 
                 6 
               
               
                 268 
                 269 
                 6 
               
               
                 269 
                 270 
                 6 
               
               
                 270 
                 271 
                 10 
               
               
                 271 
                 272 
                 7.5 
               
               
                 272 
                 273 
                 &lt;6.00 
               
               
                 273 
                 274 
                 6 
               
               
                 274 
                 275 
                 &lt;6.00 
               
               
                 275 
                 276 
                 &lt;6.00 
               
               
                 276 
                 277 
                 &lt;6.00 
               
               
                 277 
                 278 
                 &lt;6.00 
               
               
                 278 
                 279 
                 &lt;6.00 
               
               
                 279 
                 280 
                 7.5 
               
               
                 280 
                 281 
                 &lt;6.00 
               
               
                 281 
                 282 
                 &lt;6.00 
               
               
                 282 
                 283 
                 6 
               
               
                 283 
                 284 
                 6 
               
               
                 284 
                 285 
                 10 
               
               
                 285 
                 286 
                 &lt;6.00 
               
               
                 286 
                 287 
                 &lt;6.00 
               
               
                 287 
                 288 
                 7.5 
               
               
                 288 
                 289 
                 7.5 
               
               
                 289 
                 290 
                 &lt;6.00 
               
               
                 290 
                 291 
                 7.5 
               
               
                 291 
                 292 
                 &lt;6.00 
               
               
                 292 
                 293 
                 &lt;6.00 
               
               
                 293 
                 294 
                 6 
               
               
                 294 
                 295 
                 7.5 
               
               
                 295 
                 296 
                 7.5 
               
               
                 296 
                 297 
                 6 
               
               
                 297 
                 298 
                 10 
               
               
                 298 
                 299 
                 6 
               
               
                 299 
                 300 
                 &lt;15 
               
               
                 300 
                 301 
                 &lt;15 
               
               
                 301 
                 302 
                 &lt;15 
               
               
                 302 
                 303 
                 &lt;6 
               
               
                 303 
                 304 
                 &lt;6 
               
               
                   
               
            
           
         
       
     
     As shown in Table 17, several of the tested GIPR agonist peptides demonstrate high solubility in physiological buffer (Phosphate buffer at pH 7.4) of 15 mg/mL and above. Compounds 1-189 exhibit a solubility in phosphate buffer at pH 7.4 of 15 mg/mL or greater, which are the preferred compounds for dosing in volumes that facilitate once per day or QD dosing. Compounds having a solubility of less than 15 mg/mL, for example less than 15 mg/mL, or from 10 mg/mL to 15 mg/mL are less preferred, and peptide compounds having less than 10 mg/mL solubility as described in Example 16 are excluded from the GIPR agonist peptides that are suitable for QD dosing. In some embodiments, GIPR agonist peptide compounds of the present disclosure having less than 15 mg/mL solubility as described in Example 16 are excluded from the GIPR agonist peptides that are suitable for QD dosing. 
     Example 17: Summary of Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies of Selective GIP Receptor Agonist Peptides 
     Pharmacokinetic (PK) were conducted in dog in order to determine the half-life after IV and SC dosing. The peptide was dissolved in 10% DMSO/0.09% Polysorbate/PBS pH 7.4 to a concentration of 3 nmol/mL and the animal were dose with a volume of 1 mL/kg SC or IV. Blood sample were collected at 0, 0.0330, 0.0830, 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0 hours for IV dosing and 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0 for SC dosing, EDTA-K2 was used as anticoagulant. The plasma concentration of the peptide was measured using LCMS. Allometric scaling of lipidated peptide pharmacokinetics including T½ and MRT is known in the art for rodent to dog and mini pig and to humans. In one illustrative embodiment, a lipidated peptide was shown to have MRT=16.5 hrs following s.c. dosing in dog and is dosed QD in humans. See for example, Discovery and Development of Liraglutide and Semaglutide. Knudsen, L. B.; Lau, J. Frontiers in Endocrinology, 2019, vol 10, Article 155. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 shows PK data of selective compounds 
               
            
           
           
               
               
               
            
               
                   
                   
                 Dog PK 
               
               
                   
                   
                 IV &amp; SC 3 nmol/kg 
               
               
                 Cmpd 
                 SEQ 
                 IV T½ 
               
               
                 No. 
                 ID No. 
                 (SC MRT 0-last) in hours 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 17 
                 18 
                 2.6 
                 (7.3) 
               
               
                 25 
                 26 
                 5.3 
                 (9.9) 
               
               
                 21 
                 22 
                 4.6 
                 (8.7) 
               
               
                 48 
                 49 
                 7.4 
                 (15.2) 
               
               
                 142 
                 143 
                 8.4 
                 (13.8) 
               
               
                 14 
                 15 
                 4.5 
                 (8.1) 
               
               
                 20 
                 21 
                 20.6 
                 (21.8) 
               
               
                   
               
            
           
         
       
     
     As shown above in Table 18, peptide compounds 14, 17, 20, 21, 25, 48 and 142 all demonstrate exemplary pharmacokinetic activity providing the optimal exposure for once per day dosing. As shown in Table 18, the IV T½ life (data provided for dogs) can be extrapolated to human exposure ranging from IV T½ lives ranging from 6 to 16 hours when dosed at 3 nmol/kg. 
     Formulation Example 1 
       
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 (1) 
                 Compound 10 
                 10.0 mg 
               
               
                 (2) 
                 Lactose 
                 70.0 mg 
               
               
                 (3) 
                 Cornstarch 
                 50.0 mg 
               
               
                 (4) 
                 Soluble starch 
                  7.0 mg 
               
               
                 (5) 
                 Magnesium stearate 
                  3.0 mg 
               
               
                   
               
            
           
         
       
     
     Compound 10 (10.0 mg) and magnesium stearate (3.0 mg) are granulated with an aqueous soluble starch solution (0.07 mL) (7.0 mg as soluble starch), dried and mixed with lactose (70.0 mg) and cornstarch (50.0 mg). The mixture is compressed to give a tablet. 
     Formulation Example 2 
       
     
       
         
           
               
               
               
               
             
               
                   
               
             
            
               
                 (1) 
                 Compound 5 
                 5.0 
                 mg 
               
               
                 (2) 
                 Sodium chloride 
                 20.0 
                 mg 
               
               
                 (3) 
                 Distilled water to total amount 
                 2 
                 mL 
               
               
                   
               
            
           
         
       
     
     Compound 5 (5.0 mg) and sodium chloride (20.0 mg) are dissolved in distilled water, and water is added to a total amount of 2.0 ml. The solution is filtered, and filled in a 2 ml ampoule under aseptic conditions. The ampoule is sterilized and tightly sealed to give a solution for injection. 
     INDUSTRIAL APPLICABILITY 
     The GIP receptor agonist peptides of the present disclosure have superior GIP receptor selective agonist activity, and are useful as a drug for the prophylaxis or treatment of emesis and conditions caused by associated with GIP receptor activity, for example, emesis and diseases associated with vomiting or nausea and the like. In one embodiment, the selective GIP receptor agonist peptides are useful as a drug or medicament, or for use in the prophylaxis or treatment of emesis and conditions caused by associated with GIP receptor activity, for example cyclic vomiting syndrome, and nausea and/or vomiting associated with administration of a chemotherapeutic or anti-cancer agent as illustrated herein. 
     All the publications, patents, and the patent applications cited herein are incorporated herein by reference in their entireties. 
     [Free Text for Sequence Listing] 
     SEQ ID NO: 1: Natural human GIP (1-42 peptide)
 
SEQ ID NO: 2 to 305 Synthetic peptides (Formulas (I)-(III))
 
     OTHER EMBODIMENTS 
     It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.