Abstract:
The present invention is concerned with modified biological peptides providing increased potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent, either at the N-terminal of the peptide, the C-terminal of the peptide, on a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. Those peptides exhibit clinical usefulness for example in treating states of insulin resistance associated with pathologies such as type II diabetes.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention is concerned with modified peptides providing increased biological potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent either at the N-terminal of the peptide, the C-terminal of the peptide, or a free amino or carboxyl group along the peptide chain, or at a plurality of these sites.  
         BACKGROUND OF THE INVENTION  
         [0002]    Most peptides are rapidly degraded in a serum medium and as a result, their metabolites may sometimes end up with little or no residual biological activity. To increase the activity of a peptide, various techniques have been proposed. One of them is to anchor a hydrophobic chain at the N- or C-terminal of the peptidic sequence or at other residues along the peptidic chain. This technique nevertheless has limitations. For example, if the peptide comprises a long peptidic chain, the fact that a small hydrophobic group is anchored to the N- or C-terminal does not necessarily result in an increased activity of the peptide so-modified.  
           [0003]    For example, it is known that substituting OH for a more hydrophobic group like —NEt 2  at the C-terminal of a peptide sequence can result in a significantly increased specific activity. However, these results are contradicted by several publications, such as Muranichi et al. in  Pharm. Res.,  1991, 8, 649-652, which stresses the inefficiency of a lauroyl group as a hydrophobic group at the N-terminal to increase activity. Accordingly, there does not seem to be any general rule or conclusion concerning biological potency, duration of activity and/or half life, that can be derived as a result of the addition of substituents on a peptide chain, whether at the N- or C-terminal, or on certain residues along the peptidic chain.  
           [0004]    U.S. Pat. No. 6,020,311 discloses a hydrophobic growth hormone-releasing factor (GRF) analog wherein a rigidified hydrophobic moiety is coupled to the GRF peptide via an amide bond at the N-terminal of the peptide. Such analog is said to have an improved anabolic potency with reduced dosage, and a prolonged activity. According to the teaching of this patent, however, the rigidified hydrophobic moiety always comprises a carbonyl group at one extremity, which means that an amide coupling thereof to the GRF can only take place at an amino site to form the required amide bond. The patent does not mention, suggest or imply that similar results could be obtained if the amide coupling was made at the C-terminal by replacing the carbonyl group on the rigidified hydrophobic moiety with an amino group. The patent does not further mention, suggest or imply that the amide coupling could take place elsewhere on the peptide chain.  
           [0005]    Biochemistry 2001, 40, pages 2860 to 2869 describes an hydrophobic glucagon-like peptide-1 (GLP-1) analog wherein hexanoic acid, a rigidified hydrophobic moiety is coupled to the GLP-1 peptide at the N-terminal of the peptide. The results show that this analog exhibits a decreased affinity for the GLP-1 receptor, but an in vivo bioactivity similar to or slightly better than that of the wild type GLP-1, hypothetically because of increased resistance to serum degradation. According to this study, the linkage of acyl chains to His 1 , amino-acid substitutions of Ala 2 , and the addition of amino-acid sequences at the N-terminal of the molecule would be better strategies to increase the in vivo biological activity than anchoring rigidified hydrophobic chains. However, most of these strategies involve a modification of the amino-acid composition of the natural molecule, which might have negative safety consequences for clinical applications, including the risks for immunogenicity and side effects.  
           [0006]    There is therefore a great need to develop peptides modified in a manner such that their activity will be increased, thereby improving their potency, i.e., greater resistance to serum degradation and/or from hyperagonistic properties, and/or is increasing their half-life without changing the amino-acid sequence that would be clinically safe and acceptable.  
         SUMMARY OF THE INVENTION  
         [0007]    In accordance with the present invention, there is now provided a peptide of formula X n —R 1  wherein:  
           [0008]    R 1  is a peptide sequence which cannot be the GRF sequence when X represents a trans-3-hexanoyl group attached at N-terminal position of the peptide sequence;  
           [0009]    each X can be identical or independent from the others and is selected from the following list constituted by conformationally rigid moieties bearing:  
           [0010]    a) a carboxy or an amino group for coupling with the peptide sequence via an amide bond at the N-terminal of the peptide sequence, the C-terminal of the peptide sequence, at an available carboxy or amino site on the peptide sequence chain, and combinations thereof; and  
           [0011]    b) a carboxy group for coupling with the peptide sequence via an ester bond at an available hydroxy site on the peptide sequence chain, and combinations thereof;  
           [0012]    wherein,  
           [0013]    n is any digit between 1 to 5;  
           [0014]    X being defined as:  
           [0015]    i) a straight, substituted C 1 -C 10  alkyl;  
           [0016]    ii) a branched, substituted C 1 -C 10  alkyl;  
           [0017]    iii) a straight or branched, unsubstituted or substituted C 1 -C 10  alkene;  
           [0018]    iv) a straight or branched, unsubstituted or substituted C 1 -C 10  alkyne;  
           [0019]    v) an unsubstituted or substituted, saturated or unsaturated C 3 -C 10  cycloalkyl or heterocycloalkyl wherein the heteroatom is O, S or N;  
           [0020]    vi) an unsubstituted or substituted C 5 -C 14  aryl or heteroaryl wherein the heteroatom is O, S or N;  
           [0021]    wherein the substituent in the definitions i) to vi) comprises one or more  
           [0022]    a) straight or branched C 1 -C 6  alkyl;  
           [0023]    b) straight or branched C 1 -C 6  alkene;  
           [0024]    c) straight or branched C 1 -C 6  alkyne;  
           [0025]    d) C 3 -C 10  cycloalkyl or heterocycloalkyl wherein at least 2 carbon atoms are optionally connected to the C 1 -C 10  alkyl, C 1 -C 10  alkene, C 1 -C 10  alkyne, C 3 -C 10  cycloalkyl or heterocycloalkyl, and C 5 -C 14  aryl or heteroaryl; or  
           [0026]    e) C 5 -C 14  aryl or heteroaryl wherein at least 2 carbon atoms of the aryl or heteroaryl are optionally connected to the C 1 -C 10  alkyl, C 1 -C 10  alkene, C 1 -C 10  alkyne, C 3 -C 10  cycloalkyl or heterocycloalkyl, and C 5 -C 14  aryl or heteroaryl;  
           [0027]    and any isomers thereof, including cis and trans configurations, epimers, enantiomers, diastereoisomers, and racemic mixtures.  
           [0028]    The term “aryl” includes phenyl, naphthyl and the like; the term “heterocycloalkyl” includes tetrahydrofuranyl, tetrahydrothiophanyl, tetrahydrothiopyranyl, tetrahydropyranyl and partially dehydrogenated derivatives thereof, azetidinyl, piperidinyl, pyrrolidinyl, and the like; the term “heteroaryl” comprises pyridinyl, indolyl, furanyl, imidazolyl, thiophanyl, pyrrolyl, quinolinyl, isoquinolinyl, pyrimidinyl, oxazolyl, thiazolyl, isothiazolyl, isooxazolyl, pyrazolyl, and the like.  
           [0029]    The expression “conformationally rigid moiety” means an entity having limited conformational, i.e., rotational, mobility about its single bonds. Such mobility is limited, for example, by the presence of a double bond, a triple bond, or a saturated or unsaturated ring, which have little or no conformational mobility. As a result, the number of conformers or rotational isomers is reduced when compared, for example, with the corresponding straight, unsubstituted and saturated aliphatic chain. The conformationally rigid moiety may be hydrophobic, although this is not a prerequisite.  
           [0030]    According to a preferred embodiment of the present invention the peptide sequence is selected from the group consisting of Growth hormone releasing factor (GRF), Somatostatin, Glucagon-like peptide 1 (7-37), amide human (GLP-1), hGLP-1 (7-36) NH 2  Parathyroid hormone fragments such as (PTH 1-34), Adrenocorticotropic hormone (ACTH), Osteocalcin, Calcitonin, Corticotropin releasing factor, Dynorphin A, β-Endorphin, Big Gastrin-1, GLP-2, Luteinizing hormone-releasing hormone, Melanocyte Stimulating Hormone (MSH), Atrial Natriuretic Peptide, Neuromedin B, Human Neuropeptide Y, Human Orexin A, Human Peptide YY, Human Secretin, Vasoactive Intestinal peptide (VIP), Antibiotic peptides (Magainin 1, Magainin 2, Cecropin A, and Cecropin B), Substance P (SP), Beta Casomorphin-5, Endomorphin-2, Procolipase, Enterostatin, gastric inhibitory peptide, Chromogranin A, Vasostatin I &amp; II, Procalcitonin, ProNCT, ProCGRP, IL8 (monocyte-derived), GCP-2, PF4, IP-10, MIG, SDF-1α, GRO-α, I-TAC, RANTES, LD78, MIP-1α, MCP-1, MCP-2, MCP-3, MCP-4, Eotaxin, MDC, and functional derivatives or fragments thereof.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0031]    The amino acids are identified in the present application by the conventional three-letter abbreviations as indicated below, which are as generally accepted in the peptide art as recommended by the IUPAC-IUB commission in biochemical nomenclature:  
                                               Alanine   Ala   Leucine   Leu       Arginine   Arg   Lysine   Lys       Asparagine   Asn   Methionine   Met       Aspartic acid   Asp   Phenylalanine   Phe       Cyesteine   Cys   Proline   Pro       Glutamic acid   Glu   Serine   Ser       Glutamine   Gln   Threonine   Thr       Glycine   Gly   Tryptophan   Trp       Histidine   His   Tyrosine   Tyr       Isoleucine   Ile   Value   Val                  
 
           [0032]    All the peptide sequences set out herein are written according to the generally accepted convention whereby the N-terminal amino acid is on the left and the C-terminal amino acid is on the right.  
           [0033]    The present invention relates to the use of at least one conformationally rigid moiety, to produce a new family of peptides with enhanced pharmacological properties.  
           [0034]    The modified peptides of the present invention are prepared according to the following general method, well known in the art of solid phase synthesis.  
           [0035]    Conformationally rigid moieties comprising a carboxy group are used for anchoring to amino groups such as those found on the lysine side chain as well as the N-terminus of peptides. Those comprising an amino group are used for anchoring to carboxyl groups such as those found on the aspartic or glutamic acid side chains or the C-terminus of peptides. For such cases, the anchoring reaction is preferably performed on a solid phase support (Merrifield R. B. 1963,  J. Am. Chem. Soc.,  1963, 85, 2149 and  J. Am. Chem. Soc.,  1964, 86, 304) using Benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate described by Castro in the article (B. Castro et al., 1975,  Tetrahedron letters,  Vol. 14:1219).  
           [0036]    With respect to the anchoring dynamic, the preferred working temperatures are between 20° C. and 60° C. The anchoring reaction time in the case of the more hydrophobic moieties, varies inversely with temperature, and varies between 0.1 and 24 hours.  
           [0037]    Synthesis steps were carried out by solid-phase methodology on a manual peptide synthesizer using the Fmoc strategy. Fmoc amino acids were supplied by Chem Impex International Inc. Chicago and other commercial sources. Sequential Fmoc chemistry using BOP as coupling reagent was applied to the PL-Wang resin (Polymer Laboratories, catalog number: 1463-4799) for the production of the C-terminal carboxylic acid.  
           [0038]    Fmoc deprotections were accomplished with piperidine 20% solution in DMF in three consecutive steps. Always under nitrogen scrubbing, a first solution of piperidine 20% was used for 1 min. to remove the major part of the Fmoc protecting groups. Then, the solution was drained, and another fresh piperidine 20% solution was introduced this time for 3 min., drained again and finally another solution of piperidine 20% for 10 min. The peptide-resin was then washed 4 times successively with 50 mL of DMF under nitrogen scrubbing. After completion of the synthesis, the resin was well washed with DMF and DCM prior to drying.  
           [0039]    Final cleavage of side chain protecting groups and peptide-resin bonds were performed using the following mixture: TFA, ethanedithiol, triisopropylsilane, thioanisole, phenol, water (92:1.66:1.66:1.66:1:2). A final concentration of 20 mL of cleavage cocktail per gram of dried peptide-resin was used to cleave the peptide from the resin. The cleavage reaction was performed at room temperature for 2 hours. The free peptide, now in solution in the TFA cocktail, was then filtered on a coarse fritted disk funnel. The resin was then washed 3 times with pure TFA. The peptide/TFA mixture was evaporated under vacuum on a Rotary evaporator, precipitated and washed with ether prior to its dissolution in water and freeze drying to eliminate the remaining traces of solvent and scavengers.  
           [0040]    Coupling of the First Fmoc-Amino Acid to the Wang Resin  
           [0041]    We used 4-alkoxybenzyl alcohol polystyrene (Wang resin) and 2 eq of the desired Fmoc-amino acid in DMF and let both products mix together under nitrogen scrubbing for 15 min at room temperature. Then 3.3 eq of pyridine and 2 eq of 2,6-dichlorobenzoylchloride were added successively and the reaction was carried out under nitrogen scrubbing for 15-20 hours. (Seiber P., 1987,  Tetrahedron Letters,  Vol. 28, No. 49, pp 6147-6150). After this reaction, the reaction vessel was drained and the resin washed 4 times successively with DMF under nitrogen scrubbing. Any remaining hydroxyl groups of the resin were benzoylated with 3 eq of benzoylchloride and pyridine in DCE (dichloroethane) for 2 hours.  
           [0042]    Coupling of Each Remaining Amino Acid on the Growing Peptide  
           [0043]    For each of the following Fmoc-amino acid we dissolved 3 eq of the Fmoc-amino acid with 3 eq of BOP (Benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate) (B. Castro et al., 1975,  Tetrahedron letters,  Vol. 14:1219) in DMF, added the resulting solution to the resin in the reaction vessel, started the nitrogen scrubbing and added 6 eq of DIPEA (diisopropylethylamine) to start the coupling reaction. The coupling mixture was scrubbed under nitrogen for 60 min. in the reaction vessel; then drained from the vessel, the resin was washed 3 times successively with DMF and a qualitative ninhydrin test was performed to verify completion of the reaction.  
           [0044]    The coupling of the Fmoc-L-Lys(Aloc)-OH (PerSeptive Biosystems, catalog number: GEN911209), Fmoc-L-Glu(OAl)-OH (PerSeptive Biosystems, catalog number: GEN911207) and Fmoc-L-Asp(OAl)-OH (PerSeptive Biosystems, catalog number: GEN911205) were carried out in the same way as for the Fmoc-amino acids as described above.  
           [0045]    Deprotection of Allylic Groups  
           [0046]    The peptide-resin (X mmol) was then introduced in DCM under nitrogen scrubbing and after 10 min. the PdCl 2 (PPh 3 ) 2  (X mmol×0.05/0.05 eq) (palladium(II) bis-triphenylphosphine) was added to the mixture (Bürger H., Kilion W.,  J. Organometallics,  1969, 18:299). Then the (CH 3 CH 2 CH 2 ) 3 SnH (X mmol×6/6 eq) (tributyltinhydride) was diluted in DCM and added dropwise to the peptide-resin suspension with an addition funnel over a period of 30 minutes. The reaction was continued for another 10 minutes then the vessel was drained from the cleavage mixture and right after the peptide-resin was washed 4 times with DCM and 4 times with DMF (Dangles O., Guibe F., Balavoine G., Lavielle S., Marquet A., 1987,  J. Org. Chem.,  52:4984).  
           [0047]    Coupling of the Conformationally Rigid Acids and Alkylamines  
           [0048]    The coupling of the conformationally rigid acids and amines to the side chains of the peptide-resin was conducted under the same conditions as those of the Fmoc-amino acids except that for these side chain modifications we used 10 equivalents of the rigid moieties and coupling reagent instead of 3.  
           [0049]    The invention is not limited to any particular peptide sequence. Preferred peptide sequences R 1  comprise those with therapeutic properties, as well as functional derivatives or fragments thereof. The therapeutic properties of such peptides which may be used in accordance with the present invention include, without limitation, treatment of bone diseases including osteoporosis, postmenopausal osteoporosis and bone deposits, cancer treatment, regulating blood glucose, type II diabetes, treatment to enhance mucosal regeneration in patients with intestinal diseases, treatment for diseases related to inflammatory responses, obesity treatment, treatment for autism and pervasive development disorders, hyperproliferative skin conditions, aging, altering the proliferation of peripheral blood mononuclear cells, regulation of myometrial contractility and of prostaglandin release, stimulation of ACTH release, inhibition of interleukin-8 production, stimulation of acid release, enhancement of mucosal regeneration in patients with intestinal diseases, treatment for hormone-dependent diseases and conditions including for hormone-dependent cancers, modulation of melanocyte information process, involved in pressure and volume homeostasis, regulation of exocrine and endocrine secretions, smooth muscle contraction, feeding, blood pressure, blood glucose, body temperature and cell growth, regulation of food intake and energy balance, inhibition of cancer cell growth, stimulation of pancreatic secretion, or stimulate cell growth.  
           [0050]    Growth Hormone Releasing Factor (GRW):  
           [0051]    Xaa 1 -Xaa 2 -Asp-Ala-Ile-Phe-Thr-Xaa 8 -Ser-Tyr-Arg-Lys-Xaa 13 -Leu-Xaa 15 -Gln-Leu- Xaa 18 -Ala-Arg-Lys-Leu-Leu-Xaa 24 -Xaa 25 -Ile-Xaa 27 -Xaa 28 -Arg-Gln-Gln-Gly-Glu-Ser- Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH 2    
           [0052]    wherein,  
           [0053]    Xaa 1  is Tyr or His;  
           [0054]    Xaa 2  is Val or Ala;  
           [0055]    Xaa 8  is Asn or Ser;  
           [0056]    Xaa 13  is Val or Ile;  
           [0057]    Xaa 15  is Ala or Gly;  
           [0058]    Xaa 18  is Ser or Tyr;  
           [0059]    Xaa 24  is Gln or His;  
           [0060]    Xaa 25  is Asp or Glu;  
           [0061]    Xaa 27  is Met, Ile or Ile; and  
           [0062]    Xaa 28  is Ser or Asn.  
           [0063]    Somatostatin:  
                         
 
           [0064]    wherein,  
           [0065]    Xaa 12  is Tyr or Ser.  
           [0066]    Glucagon-Like Peptide 1 (7-37), (Amide Human (hGLP-1)):  
           [0067]    His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-OH(NH 2 )  
           [0068]    Parathyroid Hormone Fragments (PTH 1-34):  
           [0069]    Xaa 1 -Val-Ser-Glu-Xaa 5 -Gln-Xaa 7 -Met-His-Asn-Leu-Gly-Xaa 13 -His-Xaa 15 -Xaa 16 - Xaa 17 -Xaa 18 -Glu-Arg-Xaa 21 -Xaa 22 -Trp-Leu-Xaa 25 -Xaa 26 -Lys-Leu-Gln-Asp-Val-His- Xaa 33 -Xaa 34 -NH 2    
           [0070]    wherein,  
           [0071]    Xaa 1  is Ser or Ala;  
           [0072]    Xaa 5  is Ile or Met;  
           [0073]    Xaa 7  is Leu or Phe;  
           [0074]    Xaa 13  is Lys or Glu;  
           [0075]    Xaa 15  is Leu or Arg;  
           [0076]    Xaa 16  is Asn or Ala or Ser or His;  
           [0077]    Xaa 17  is Ser of Thr;  
           [0078]    Xaa 18  is Met or Val or Leu;  
           [0079]    Xaa 21  is Val or met or Gln;  
           [0080]    Xaa 22  is Glu or Gln or Asp;  
           [0081]    Xaa 25  is Arg or Gln;  
           [0082]    Xaa 26  is Lys or Met;  
           [0083]    Xaa 33  is Asn or Ser; and  
           [0084]    Xaa 34  is Phe or Ala.  
           [0085]    Adrenocorticotropic Hormone (ACTH):  
           [0086]    Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Xaa 13 -Gly-Xaa 15 -Lys-Arg-Arg- Pro-Xaa 20 -Lys-Val-Tyr-Pro-Asn-Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -Glu-Xaa 31 -Xaa 32 -Glu- Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Glu-Xaa 39 -NH 2    
           [0087]    wherein,  
           [0088]    Xaa 13  is Val or Met;  
           [0089]    Xaa 15  is Lys or Arg;  
           [0090]    Xaa 20  is Val or Ile;  
           [0091]    Xaa 26  is Gly or Ser;  
           [0092]    Xaa 27  is Ala or Phe or Val;  
           [0093]    Xaa 28  is Glu or Gln;  
           [0094]    Xaa 29  is Asp or Asn or Glu;  
           [0095]    Xaa 31  is Ser or Thr;  
           [0096]    Xaa 32  is Ala or Val or Ser;  
           [0097]    Xaa 34  is Ala or Asn or Gly;  
           [0098]    Xaa 35  is Phe or Met;  
           [0099]    Xaa 36  is Pro or Gly;  
           [0100]    Xaa 37  is Leu or Val or Pro; and  
           [0101]    Xaa 39  is Phe or Val or Leu.  
           [0102]    Osteocalcin:  
           [0103]    Tyr-Leu-Xaa 52 -Xaa 53 -Xaa 54 -Leu-Gly-Ala-Pro-Xaa 59 -Pro-Tyr-Pro-Asp-Pro-Leu-Glu- Pro-Xaa 68 -Arg-Glu-Val-Cys-Glu-Leu-Asn-Pro-Xaa 77 -Cys-Asp-Glu-Leu-Ala-Asp- His-Ile-Gly-Phe-Gln-Xaa 89 -Ala-Tyr-Xaa 92 -Arg-Xaa 94 -Tyr-Gly-Xaa 97 -Val-NH 2    
           [0104]    wherein,  
           [0105]    Xaa 52  is Tyr or Asp or Asn;  
           [0106]    Xaa 53  is Gln or His or Asn;  
           [0107]    Xaa 54  is Trp or Gly;  
           [0108]    Xaa 59  is Val or Ala;  
           [0109]    Xaa 68  is Arg or Lys or His;  
           [0110]    Xaa 77  is Asp or Asn;  
           [0111]    Xaa 89  is Glu or Asp;  
           [0112]    Xaa 92  is Arg or Lys;  
           [0113]    Xaa 94  is Phe or Ile; and  
           [0114]    Xaa 97  is Pro or Thr.  
           [0115]    Calcitonin:  
           [0116]    Cys-Xaa 86 -Xaa 87 -Leu-Ser-Thr-Cys-Xaa 92 -Leu-Gly-Xaa 95 -Xaa 96 -Xaa 97 -Xaa 98 -Xaa 99 - Xaa 100 -Xaa 101 -Xaa 102 -Xaa 103 -Xaa 104 -Thr-Xaa 106 -Xaa 107 -Xaa 108 -Xaa 109 - Xaa 110 -Xaa 111 -Gly-Xaa 113 -Xaa 114 -Xaa 115 -Pro-NH 2    
           [0117]    wherein,  
           [0118]    Xaa 86  is Gly or Ser or Ala;  
           [0119]    Xaa 87  is Asn or Ser;  
           [0120]    Xaa 92  is Met or Val;  
           [0121]    Xaa 95  is Thr or Lys;  
           [0122]    Xaa 96  is Tyr or Leu;  
           [0123]    Xaa 97  is Thr or Ser;  
           [0124]    Xaa 98  is Gln or Lys;  
           [0125]    Xaa 99  is Asp or Glu;  
           [0126]    Xaa 100  is Phe or Leu;  
           [0127]    Xaa 101  is Asn or His;  
           [0128]    Xaa 102  is Lys or Asn;  
           [0129]    Xaa 103  is Phe or Leu;  
           [0130]    Xaa 104  is His or Gln;  
           [0131]    Xaa 106  is Phe or Tyr;  
           [0132]    Xaa 107  is Pro or Ser;  
           [0133]    Xaa 108  is Gln or Gly or Arg;  
           [0134]    Xaa 109  is Thr or Ile;  
           [0135]    Xaa 110  is Ala or Gly or Ser or Asp or Asn;  
           [0136]    Xaa 111  is Ile or Phe or Val or Thr;  
           [0137]    Xaa 113  is Val or Ala or Ser;  
           [0138]    Xaa 114  is Gly or Glu; and  
           [0139]    Xaa 115  is Ala or Thr.  
           [0140]    Corticotropin Releasing Factor:  
           [0141]    Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu- Glu-Met-Xaa 101 -Xaa 102 -Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH 2    
           [0142]    wherein,  
           [0143]    Xaa 101  is Ala or Pro; and  
           [0144]    Xaa 102  is Arg or Gly.  
           [0145]    Dynorphin A:  
           [0146]    H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH  
           [0147]    β-Endorphin:  
           [0148]    H-Tyr-Gly-Gly-Phe-Met-Thr-Xaa 243 -Glu-Xaa 245 -Ser-Gln-Thr-Pro-Leu-Xaa 251 -Thr- Leu-Phe-Lys-Asn-Ala-Ile-Xaa 259 -Lys-Asn-Xaa 262 -Xaa 263 -Lys-Lys-Gly-Xaa 267 -OH  
           [0149]    wherein,  
           [0150]    Xaa 243  is Ser or Pro;  
           [0151]    Xaa 245  is Lys or Arg;  
           [0152]    Xaa 251  is Val or Met;  
           [0153]    Xaa 259  is Ile or Val;  
           [0154]    Xaa 262  is Ala or Thr or Ser or Val;  
           [0155]    Xaa 263  is Tyr or His; and  
           [0156]    Xaa 267  is Glu or Leu or Gln or His.  
           [0157]    Big Gastrin-1:  
           [0158]    pXaa 59 -Leu-Gly-Xaa 62 -Gln-Xaa 64 -Xaa 65 -Xaa 66 -Xaa 67 -Xaa 68 -Xaa 69 -Ala-Asp-Xaa 72 - Xaa 73 -Lys-Lys-Xaa 76 -Xaa 77 -Pro-Xaa 79 -Xaa 80 -Glu-Xaa 82 -Glu-Glu-Xaa 85 -Ala-Tyr-Gly- Trp-Met-Asp-Phe-NH 2    
           [0159]    wherein,  
           [0160]    Xaa 59  is Glu or Gln;  
           [0161]    Xaa 62  is Pro or Leu;  
           [0162]    Xaa 64  is Gly or Asp;  
           [0163]    Xaa 65  is Pro or Ser;  
           [0164]    Xaa 66  is Pro or Gln;  
           [0165]    Xaa 67  is His or Gln;  
           [0166]    Xaa 68  is Leu or Met or Phe or Gln;  
           [0167]    Xaa 69  is Val or Ile;  
           [0168]    Xaa 72  is Pro or Leu;  
           [0169]    Xaa 73  is Ser or Ala;  
           [0170]    Xaa 76  is Gln or Glu;  
           [0171]    Xaa 77  is Gly or Arg;  
           [0172]    Xaa 79  is Trp or Pro or Arg;  
           [0173]    Xaa 80  is Leu or Val or Met;  
           [0174]    Xaa 82  is Glu or Lys; and  
           [0175]    Xaa 85  is Glu or Ala.  
           [0176]    GLP-2:  
           [0177]    His-Ala-Asp-Gly-Ser-Phe-Xaa 152 -Xaa 153 -Xaa 154 -Xaa 155 -Xaa 156 -Xaa 157 -Xaa 158 -Leu-Asp- Xaa 161- Xaa 162 -Ala-Xaa 164 -Xaa 165 -Xaa 166 -Phe-Xaa 168 -Xaa 169 -Trp-Xaa 171 -Xaa 172 - Xaa 173 -Thr-Xaa 175 -Xaa 176 -Xaa 177 -Xaa 178 ;  
           [0178]    wherein,  
           [0179]    Xaa 152  is Ser or Thr;  
           [0180]    Xaa 153  is Asp or Ser;  
           [0181]    Xaa 154  is Glu or Asp;  
           [0182]    Xaa 155  is Met or Phe;  
           [0183]    Xaa 156  is Asn or Ser;  
           [0184]    Xaa 157  is Thr or Lys;  
           [0185]    Xaa 158  is Ile or Val or Ala;  
           [0186]    Xaa 161  is Asn or Ile or His or Ser;  
           [0187]    Xaa 162  is Leu or Lys;  
           [0188]    Xaa 164  is Ala or Thr;  
           [0189]    Xaa 165  is Arg or Gln or Lys;  
           [0190]    Xaa 166  is Asp or Glu;  
           [0191]    Xaa 168  is Ile or Leu;  
           [0192]    Xaa 169  is Asn or Asp;  
           [0193]    Xaa 171  is Leu or Ile;  
           [0194]    Xaa 172  is Ile or Leu;  
           [0195]    Xaa 173  is Gln or Asn or His;  
           [0196]    Xaa 175  is Lys or Pro;  
           [0197]    Xaa 176  is Ile or Val;  
           [0198]    Xaa 177  is Thr or Lys; and  
           [0199]    Xaa 178  is Asp or Glu.  
           [0200]    Luteinizing Hormone-Releasing Hormone:  
           [0201]    Xaa 1 -His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH  
           [0202]    wherein,  
           [0203]    Xaa 1  is pGlu, 5-oxoPro or Gln.  
           [0204]    Melanocyte Stimulating Hormone (MSH):  
           [0205]    Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2    
           [0206]    Atrial Natriuretic Peptide:  
           [0207]    H-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Xaa 135 -Asp-Arg-Ile-Gly-Ala-Gln-Ser-Xaa 142 -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-OH  
           [0208]    wherein,  
           [0209]    Xaa 135  is Met or Ile; and  
           [0210]    Xaa 142  is Gly or Ser.  
           [0211]    Neuromedin B:  
           [0212]    H-Gly-Asn-Leu-Trp-Ala-Thr-Gly-His-Phe-Met-NH 2    
           [0213]    Human Neuropeptide Y:  
           [0214]    H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-asp-Met-Ala- Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH 2    
           [0215]    Human Orexin A:  
           [0216]    pGlu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu- Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH 2    
           [0217]    Human Peptide YY:  
           [0218]    H-Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn- Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2    
           [0219]    Human Secretin:  
           [0220]    H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH 2    
           [0221]    Vasoactive Intestinal Peptide (VIP):  
           [0222]    H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH 2    
           [0223]    Antibiotic Peptides such as:  
                           Magainin 1:           Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Gly-Lys-Phe-               Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Lys-Ser               Magainin 2:       Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-               Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Asn-Ser               Cecropin A:       Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-               Gln-Ala-Thr-Gln-Ile-Ala-Lys               Cecropin B:       Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Met-Gly-               Arg-Asn-Ile-Arg-Asn-Gly-Ile-Val-Lys-Ala-Gly-Pro-               Ala-Ile-Ala-Val-Leu-Gly-Glu-Ala-Lys-Ala-Leu.               Substance P (SP):       Arg-Pro-Leu-Pro-Gln-Glu-Phe-Phe-Gly-Leu-Met-amide               Beta Casomorphin-5:       Tyr-Pro-Phe-Pro-Gly               Endomorphin-2:       Tyr-Pro-Phe-Phe-NH2               Procolipase:       100 aa peptide (X1-Pro-X2-Pro-Arg . . . )               Enterostatin       Val-Pro-Asp-Pro-Arg               Gastrin Inhibitory Peptide:       Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-               Ala-    Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe- Val-               Asn-Trp-Leu- Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-               Trp-Lys-His-Asn-Ile-Thr-Gln          
 
           [0224]    Chromogranin A  
           [0225]    Vasostatin I  
           [0226]    Vasostatin II:  
                                       Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr                           Glu Val Met Lys Cys Ile Val Glu Val Ile Ser Asp                       Thr Leu Ser Lys Pro Ser Pro Met Pro Val Ser Gln                       Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg Ile                       Leu Ser Ile Leu Arg His Gln Asn Leu Leu Lys Glu                       Leu Gln Asp Leu Ala Leu Gln Gly Ala Lys Glu Arg                       Ala His Gln Gln Lys Lys His Ser Gly Phe Glu Asp                       Glu Leu Ser Glu Val Leu Glu Asn Gln Ser Ser Gln                       Ala Glu Leu Lys Glu Ala Val Glu Glu Pro Ser Ser                       Lys Asp Val Met Glu          
 
           [0227]    Procalcitonin  
           [0228]    ProNCT  
           [0229]    ProCGRP  
           [0230]    Chemokine Family:  
           [0231]    CXC-Group:  
           [0232]    IL8(Monocyte-Derived):  
           [0233]    SerAlaLysGluLeuArgCysGlnCys . . .  
           [0234]    GCP-2:  
           [0235]    GlyProValSerAlaValLeuThrGluLeuArgCysThrCys . . .  
           [0236]    PF4:  
           [0237]    GluAlaGluGluAspGlyAspLeuGlnCysLeuCys . . .  
           [0238]    IP-10:  
           [0239]    ValProLeuSerArgThrValArgCCysThrCys . . .  
           [0240]    MIG:  
           [0241]    ThrProValValArgLysGlyArgCysSerCys . . .  
           [0242]    SDF-1α:  
           [0243]    LysProValSerLeuSerTyrArgCysProCys . . .  
           [0244]    GROα:  
           [0245]    AlaProLeuAlaThrGluLeuArgCysGlnCys . . .  
           [0246]    I-TAC:  
           [0247]    PheProMetPheLysLysGlyArgCysLeuCys . . .  
           [0248]    CC-Group:  
           [0249]    RANTES:  
           [0250]    SerProTyrSerSerAspThrThrProCys . . .  
           [0251]    LD78:  
           [0252]    AlaProLeuAlaAlaAspThrProThrAlaCys . . .  
           [0253]    MIP-1α:  
           [0254]    AlaProMetGlySerAspProProThrAlaCys . . .  
           [0255]    MCP-1:  
           [0256]    GlnProAspAlaIleAsnAlaProValThrCys . . .  
           [0257]    MCP-2:  
           [0258]    GlnProSerAspValSerIleProIleThrCys . . .  
           [0259]    MCP-3:  
           [0260]    GlnProValGlyIleTAsnSeerThrThrCys . . .  
           [0261]    MCP-4:  
           [0262]    GlnProAspAlaLeuAspValProSerThrCys . . .  
           [0263]    Eotaxin:  
           [0264]    GlyProAlaSerValProThrThrCys . . .  
           [0265]    MDC:  
           [0266]    GlyProTyrGlyAlaAsnMetGluAspSerValCys . . .  
           [0267]    and functional derivatives or fragments thereof.  
           [0268]    The complete definition of the previously listed sequences are known inter alia from Mentlein, R (1999) Regul. Pept. 85:9-24 and from De Meester, I. Et al. (2000) Adv ExpMed Biol. 477:67-87. Those documents are incorporated by reference to the present application.  
           [0269]    In a more preferred embodiment, the peptide is substituted with one or more conformationally rigid moieties. Preferred structures of the conformationally rigid moieties comprise those with a double bond, a triple bond or a saturated or unsaturated ring.  
           [0270]    The following is a brief list of the formula of preferred conformationally rigid moieties, identified as Formula 1 to 63, which are suitable for the purposes of the present invention.  
           [0271]    Among the preferred modified peptides according to the present invention, are those wherein the peptide sequence is the sequence of a natural peptide.  
                         

                         

                         

                         

                         

                         

                         
 
           [0272]    wherein, R is hydrogen, CH 3  or CH 2 CH 3 .  
           [0273]    A preferred embodiment of the present invention is constituted by peptides wherein the peptide sequence is Somatostatin and at least one conformationally rigid moiety is coupled with said somatostatin peptide sequence via an amide bond at different positions as follows:  
                                                 Position   conformationally rigid moieties                                                Ala 1                                               Asp 5                                                                             Cys 14                                               Ala 1  + Cys 14                                                                                
 
           [0274]    An another preferred embodiment of the present invention is constituted by those peptides wherein the peptide sequence is PTH 1-34 and at least one conformationally rigid moiety is coupled with said PTH 1-34 peptide sequence via an amide bond at different positions as follows:  
                                                 Position   conformationally rigid moieties                                                Ser 1                                                                             Glu 4                                                                             Lys 26                                                                             Lys 27                                                                             Asp 30                                                                             Ser 1  +Lys 27                                                                                
 
           [0275]    A further preferred embodiment of the present invention is constituted by those peptides wherein the peptide sequence is GLP-1 and at least one conformationally rigid moiety is coupled with said GLP-1 peptide sequence via an amide bond at different positions as follows:  
                                                 Position   conformationally rigid moieties                                                His 1                                                                                                                                                                                                       Glu 3                                                                             Asp 9                                                                             His 1  + Glu 3                                                                             His 1  + Asp 9                                                                             Glu 3  + Asp 9                                                                                
 
           [0276]    Also preferred among the modified peptides according to the invention are those peptides wherein;  
           [0277]    the peptide sequence is GLP-2 and at least one conformationally rigid moiety is coupled with said GLP-2 peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0278]    the peptide sequence is Enterostatin and at least one conformationally rigid moiety is coupled with said Enterostatin peptide sequence via an amide bond at different positions of the peptide sequence;  
           [0279]    the peptide sequence is NPY and at least one conformationally rigid moiety is coupled with said NPY peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0280]    the peptide sequence is NPYY and at least one conformationally rigid moiety is coupled with said NPYY peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0281]    the peptide sequence is Secretin and at least one conformationally rigid moiety is coupled with said Secretin peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0282]    the peptide sequence is Vasoactive Intestinal Peptide and at least one conformationally rigid moiety is coupled with said Vasoactive Intestinal Peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0283]    the peptide sequence is Gastrin Inhibitory Peptide and at least one conformationally rigid moieties is coupled with said Gastrin inhibitory Peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0284]    the peptide sequence is Vasostatin II and at least one conformationally rigid moiety is coupled with said Vasostatin II peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0285]    the peptide sequence is RANTES and at least one conformationally rigid moiety is coupled with said RANTES peptide sequence via an amide or ester bond at different positions of the peptide sequence;  
           [0286]    the peptide sequence is Eotaxin and at least one conformationally rigid moiety is coupled with said Eotaxin peptide sequence via an amide or ester bond at different positions of the peptide sequence.  
           [0287]    In the modified peptides of the invention, the conformationally rigid moiety is preferably coupled with said peptide sequence via an amide bond at the N-terminal.  
           [0288]    The modified peptides according to the invention, wherein the conformationally rigid moiety is the formula referenced 60 in the description, are of a particular interest.  
           [0289]    The modified peptides of the present invention can be administered in various ways, such as for example, intravenously, subcutaneously, intradermally, transdermally, intraperitoneally, orally, or topically. The modified peptides of the present invention can also be administered by inhalation, when in a powder form or aerosol form. Furthermore, pharmaceutically acceptable carriers for delivery of modified peptides of the present invention include, without limitation, liposome, nanosome, patch, implant or any delivery devices.  
           [0290]    In addition to the carboxy and amino groups present at the C- and N-terminals respectively of the peptide, other carboxy and amino sites can be available on the peptide chain. For example, if the peptide chain comprises amino acids provided with a carboxylic acid side chain such as aspartic acid and glutamic acid, additional carboxy sites will therefore be available on the chain for amidation. Should the peptide chain comprise amino acids with a carboxamide side chain such as asparagine and glutamine, these also provide additional carboxy groups for amidation by a conformationally rigid moiety, provided that they are accessed synthetically via the corresponding aspartic and glutamic acids. Further, if the peptide comprises amino acids provided with a basic side chain such as arginine, histidine or lysine, additional amino sites will then be available on the chain for amidation by a conformationally rigid moiety. The peptide chain may also include both acidic and basic amino acids, meaning that the conformationally rigid substituents could be coupled to the peptide chain via the N-terminal, the C-terminal, a carboxy site on the peptide chain, an amino site on the peptide chain, or a plurality of these sites.  
           [0291]    The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope. 
       
    
    
     EXAMPLE 1  
       [0292]    Synthesis of GLP-1 Analogs  
         [0293]    In accordance with the present invention, at least one of the following conformationally rigid moiety is coupled with the GLP-1 peptide sequence via an amide bond at different positions as follows.  
                                                 Position   conformationally rigid moieties                                                His 1                                                                                                                                                                                                          
 
         [0294]    hGLP-1 (7-37) Analogs Synthesis  
         [0295]    hGLP-1 (7-37) derivatives modified at the amino terminus with rigid hydrophobic moieties were synthesized using Fmoc chemistry (1), on the Symphony apparatus (Rainin Instrument Co., Inc.). Fmoc-Gly-Wang resin (0.70 mmole/g) and five equivalents of reagents (100 μm scale, amino acids concentration of 200 mM), were used with a time coupling of 30 minutes. The reactions have been monitored by the Kaiser test. The three conformationally rigid moieties introduced at the N-terminus of the hGLP-1 (7-37) are:  
         [0296]    Peptide # 1=(O-Tolylacetic acid-His 7 )-hGLP-1 (7-37) [O-Tolylacetic acid (13) (10 equivalents per coupling; coupling time 45 min)] 
         [0297]    Peptide # 2=((+,−)-cis-2-Ethylcyclopropylacetic acid -His 7 )-hGLP-1 (7-37) [(+,−)-cis-2-Ethylcyclopropylacetic acid (60) (7.5 equivalents per coupling: coupling time 60 min)].  
         [0298]    The peptides were cleaved using a TFA cocktail (92% TFA, 2% ethanedithiol, 2% thioanisole, 2% triisopropylsilane, 2% water, 2% (w/v) phenol) for 2 hours. All the analogs have been purified by reverse-phase HPLC. They have been analyzed by analytical HPLC and by MS (MALDI-TOF).  
         [0299]    The synthesis of GLP-1 analogs is well known to the person skilled in the art and is fuirther illustrated by the general references Fmoc Solid Phase Peptide Synthesis. A Practical Approach (2000). Chan, W. C. and White, P. D., Oxford University Press, New York, USA, 346p which are incorporated by reference.  
         [0300]    Biological Assess of GLP-1 Analogs  
         [0301]    Materials &amp; Methods  
         [0302]    Oral Glucose Tolerance Test (OGTT)  
         [0303]    Six-week old female CD1 mice (Charles River) were fasted for at least 16 hours. Mice were given 1.5 mg of glucose per gram of body weight orally in water through a gastric savage tube at t=o min and blood was collected from a tail vein at t=0, 10, 20, 30, 60, 90 and 120 min for measurement of blood glucose using a glucose meter (Lifescan). Peptides or vehicle were injected subcutaneously 5 min prior to the glucose administration. Data were expressed as the area under the curve, calculated from the change (delta) in blood glucose for each time, using the trapezoidal rule. Therefore, the data represent the integrated increase in blood glucose over a 120 min period following glucose administration. Data presented are the mean±SEM of 4 to 11 animals per group.  
         [0304]    Test Articles  
         [0305]    All peptides, including wild-type GLP-1 (7-37), were tested in the OGTT test at 3 different concentrations: 1, 5 and 10 ug per mouse. In a first set of experiments (study A), peptide 3 was tested in comparison with vehicle and hGLP-1(7-37). In a second set of experiments (study B), peptides 1 and 2 were tested in comparison with vehicle and hGLP-1 (7-37).  
         [0306]    wt GLP1: hGLP(7-37)  
         [0307]    Peptide #1: (O-Tolylacetic acid-His 7 )-hGLP-1 (7-37)  
         [0308]    Peptide #2: ((+,−)-cis-2-Ethylcyclopropylacetic acid-His 7 )-hGLP-1 (7-37)  
         [0309]    Peptide #3: (Hexanoyl-trans-3-His 7 )-hGLP-1 (7-37)  
         [0310]    Results and Conclusions  
         [0311]    Results are shown in FIG. I (study A) and FIG. II (study B)  
         [0312]    In studies A and B, administration of vehicle resulted in a similar integrated response in glucose levels (study A: 380±57 vs study B: 309±68 mM×120 min), illustrating the validity and reproducibility of the methodology. Although wt GLP-1 induced a dose-related decrease in the glucose response, this peptide was not able to completely suppress the glucose response at any dose, which might be interpreted as a limitation in its potential clinical usefulness. In contrast, peptide 3 (study A, FIG. 1) was able to completely abolish the glucose response, but only at the 10 ug dose (9±26 mM×120 min). Surprisingly, peptide 2 (study B, FIG. 2) was even more potent than peptide 3, being able to totally prevent the glucose response both at the 5 ug and the 10 ug doses (5 ug: −17±67 mM×120 min; 10 ug: 61±64 mM×120 min). In conclusion, the GLP-1 analog corresponding to peptide 2 was identified with marked increased biological potency over the wild type GLP-1 (7-37), because of this increased potency, this peptide may have clinical usefulness in treating states of insulin resistance associated with pathologies such as type II diabetes.  
                                                 Position   conformationally rigid moieties                                                Glu 3                                                                             Asp 9                                                                             His 1  + Glu 3                                                                             His 1  + Asp 9                                                                             Glu 3  + Asp 9                                                                                
 
       EXAMPLE 2  
       [0313]    PTH 1-34 Analogs  
         [0314]    In accordance with the present invention, at least one of the following conformationally rigid moiety is coupled with the PTH 1-34 peptide sequence via an amide bond at different positions as follows.  
                                                 Position   conformationally rigid moieties                                                Ser 1                                                                             Glu 4                                                                             Lys 26                                                                             Lys 27                                                                             Asp 30                                                                             Ser 1  +Lys 27                                                                                
 
       EXAMPLE 3  
       [0315]    Somatostatin Analogs  
         [0316]    In accordance with the present invention, at least one of the following conformationally rigid moiety is coupled with the somatostatin peptide sequence via an amide bonds at different position as follows.  
                                                 Position   conformationally rigid moieties                                                Ala 1                                               Asp 5                                                                             Cys 14                                               Ala 1  + Cys 14                                                                                
 
         [0317]    While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention, and including such departures from the present description as come within known or customary practice within the art to which the invention pertains, and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.  
     
       
       
         1 
         
           
             50  
           
           
             1  
             44  
             PRT  
             human  
             
               VARIANT  
               (1)...(1)  
               Xaa = Tyr or His  
             
           
            1 

Xaa Xaa Asp Ala Ile Phe Thr Xaa Ser Tyr Arg Lys Xaa Leu Xaa Gln 
 1               5                  10                  15 

Leu Xaa Ala Arg Lys Leu Leu Xaa Xaa Ile Xaa Xaa Arg Gln Gln Gly 
            20                  25                  30 

Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu 
        35                  40 

 
           
             2  
             8  
             PRT  
             human  
             
               DISULFID  
               (3)...(3)  
               Disulfide linkage with amino acid 1 (Cys) of 
      SEQ ID NO 3  
             
           
            2 

Ala Gly Cys Lys Asn Phe Phe Trp 
 1               5 

 
           
             3  
             6  
             PRT  
             human  
             
               DISULFID  
               (1)...(1)  
               Disulfide linkage with amino acid 3 (Cys) of 
      SEQ ID NO 2  
             
           
            3 

Cys Ser Xaa Phe Thr Lys 
 1               5 

 
           
             4  
             31  
             PRT  
             human  
           
            4 

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 
 1               5                  10                  15 

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 
            20                  25                  30 

 
           
             5  
             34  
             PRT  
             human  
             
               VARIANT  
               (1)...(1)  
               Xaa = Ser or Ala  
             
           
            5 

Xaa Val Ser Glu Xaa Gln Xaa Met His Asn Leu Gly Xaa His Xaa Xaa 
 1               5                  10                  15 

Xaa Xaa Glu Arg Xaa Xaa Trp Leu Xaa Xaa Lys Leu Gln Asp Val His 
            20                  25                  30 

Xaa Xaa 

 
           
             6  
             39  
             PRT  
             human  
             
               VARIANT  
               (13)...(13)  
               Xaa = Val or Met  
             
           
            6 

Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Xaa Gly Xaa Lys 
 1               5                  10                  15 

Arg Arg Pro Xaa Lys Val Tyr Pro Asn Xaa Xaa Xaa Xaa Glu Xaa Xaa 
            20                  25                  30 

Glu Xaa Xaa Xaa Xaa Glu Xaa 
        35 

 
           
             7  
             49  
             PRT  
             human  
             
               VARIANT  
               (3)...(3)  
               Xaa = Tyr or Asp or Asn  
             
           
            7 

Tyr Leu Xaa Xaa Xaa Leu Gly Ala Pro Xaa Pro Tyr Pro Asp Pro Leu 
 1               5                  10                  15 

Glu Pro Xaa Arg Glu Val Cys Glu Leu Asn Pro Xaa Cys Asp Glu Leu 
            20                  25                  30 

Ala Asp His Ile Gly Phe Gln Xaa Ala Tyr Xaa Arg Xaa Tyr Gly Xaa 
        35                  40                  45 

Val 

 
           
             8  
             32  
             PRT  
             human  
             
               VARIANT  
               (2)...(2)  
               Xaa = Gly or Ser or Ala  
             
           
            8 

Cys Xaa Xaa Leu Ser Thr Cys Xaa Leu Gly Xaa Xaa Xaa Xaa Xaa Xaa 
 1               5                  10                  15 

Xaa Xaa Xaa Xaa Thr Xaa Xaa Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Pro 
            20                  25                  30 

 
           
             9  
             41  
             PRT  
             human  
             
               VARIANT  
               (22)...(22)  
               Xaa = Ala or Pro  
             
           
            9 

Ser Glu Glu Pro Pro Ile Ser Leu Asp Leu Thr Phe His Leu Leu Arg 
 1               5                  10                  15 

Glu Val Leu Glu Met Xaa Xaa Ala Glu Gln Leu Ala Gln Gln Ala His 
            20                  25                  30 

Ser Asn Arg Lys Leu Met Glu Ile Ile 
        35                  40 

 
           
             10  
             17  
             PRT  
             human  
           
            10 

Tyr Gly Gly Phe Leu Arg Arg Ile Arg Pro Lys Leu Lys Trp Asp Asn 
 1               5                  10                  15 

Gln 

 
           
             11  
             31  
             PRT  
             human  
             
               VARIANT  
               (7)...(7)  
               Xaa = Ser or Pro  
             
           
            11 

Tyr Gly Gly Phe Met Thr Xaa Glu Xaa Ser Gln Thr Pro Leu Xaa Thr 
 1               5                  10                  15 

Leu Phe Lys Asn Ala Ile Xaa Lys Asn Xaa Xaa Lys Lys Gly Xaa 
            20                  25                  30 

 
           
             12  
             34  
             PRT  
             human  
             
               VARIANT  
               (1)...(1)  
               Xaa = para-Glu or para-Gln  
             
           
            12 

Xaa Leu Gly Xaa Gln Xaa Xaa Xaa Xaa Xaa Xaa Ala Asp Xaa Xaa Lys 
 1               5                  10                  15 

Lys Xaa Xaa Pro Xaa Xaa Glu Xaa Glu Glu Xaa Ala Tyr Gly Trp Met 
            20                  25                  30 

Asp Phe 

 
           
             13  
             33  
             PRT  
             human  
             
               VARIANT  
               (7)...(7)  
               Xaa = Ser or Thr  
             
           
            13 

His Ala Asp Gly Ser Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Asp Xaa 
 1               5                  10                  15 

Xaa Ala Xaa Xaa Xaa Phe Xaa Xaa Trp Xaa Xaa Xaa Thr Xaa Xaa Xaa 
            20                  25                  30 

Xaa 

 
           
             14  
             10  
             PRT  
             human  
             
               VARIANT  
               (1)...(1)  
               Xaa = pGlu or 5-oxoPro or Gln  
             
           
            14 

Xaa His Trp Ser Tyr Gly Leu Arg Pro Gly 
 1               5                  10 

 
           
             15  
             13  
             PRT  
             human  
             
               ACETYLATION  
               (1)...(1)  
             
             
               AMIDATION  
               (13)...(13)  
             
           
            15 

Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val 
 1               5                  10 

 
           
             16  
             28  
             PRT  
             human  
             
               VARIANT  
               (12)...(12)  
               Xaa = Met or Ile  
             
           
            16 

Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Xaa Asp Arg Ile Gly 
 1               5                  10                  15 

Ala Gln Ser Xaa Leu Gly Cys Asn Ser Phe Arg Tyr 
            20                  25 

 
           
             17  
             10  
             PRT  
             human  
             
               AMIDATION  
               (10)...(10)  
             
           
            17 

Gly Asn Leu Trp Ala Thr Gly His Phe Met 
 1               5                  10 

 
           
             18  
             36  
             PRT  
             human  
             
               AMIDATION  
               (35)...(35)  
             
           
            18 

Tyr Pro Ser Lys Pro Asp Asn Pro Gly Glu Asp Ala Pro Ala Glu Asp 
 1               5                  10                  15 

Met Ala Arg Tyr Tyr Ser Ala Leu Arg His Tyr Ile Asn Leu Ile Thr 
            20                  25                  30 

Arg Gln Arg Tyr 
        35 

 
           
             19  
             33  
             PRT  
             human  
             
               VARIANT  
               (1)...(1)  
               Glu is para-Glu  
             
           
            19 

Glu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu 
 1               5                  10                  15 

Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr 
            20                  25                  30 

Leu 

 
           
             20  
             36  
             PRT  
             human  
             
               AMIDATION  
               (36)...(36)  
             
           
            20 

Tyr Pro Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu 
 1               5                  10                  15 

Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr 
            20                  25                  30 

Arg Gln Arg Tyr 
        35 

 
           
             21  
             27  
             PRT  
             human  
             
               AMIDATION  
               (27)...(27)  
             
           
            21 

His Ser Asp Gly Thr Phe Thr Ser Glu Leu Ser Arg Leu Arg Glu Gly 
 1               5                  10                  15 

Ala Arg Leu Gln Arg Leu Leu Gln Gly Leu Val 
            20                  25 

 
           
             22  
             28  
             PRT  
             human  
             
               AMIDATION  
               (28)...(28)  
             
           
            22 

His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln 
 1               5                  10                  15 

Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn 
            20                  25 

 
           
             23  
             23  
             PRT  
             human  
           
            23 

Gly Ile Gly Lys Phe Leu His Ser Ala Gly Lys Phe Gly Lys Ala Phe 
 1               5                  10                  15 

Val Gly Glu Ile Met Lys Ser 
            20 

 
           
             24  
             23  
             PRT  
             human  
           
            24 

Gly Ile Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe 
 1               5                  10                  15 

Val Gly Glu Ile Met Asn Ser 
            20 

 
           
             25  
             19  
             PRT  
             human  
           
            25 

Lys Trp Lys Val Phe Lys Lys Ile Glu Lys Val Gly Gln Ala Thr Gln 
 1               5                  10                  15 

Ile Ala Lys 

 
           
             26  
             35  
             PRT  
             human  
           
            26 

Lys Trp Lys Val Phe Lys Lys Ile Glu Lys Met Gly Arg Asn Ile Arg 
 1               5                  10                  15 

Asn Gly Ile Val Lys Ala Gly Pro Ala Ile Ala Val Leu Gly Glu Ala 
            20                  25                  30 

Lys Ala Leu 
        35 

 
           
             27  
             11  
             PRT  
             human  
             
               AMIDATION  
               (11)...(11)  
             
           
            27 

Arg Pro Leu Pro Gln Glu Phe Phe Gly Leu Met 
 1               5                  10 

 
           
             28  
             5  
             PRT  
             human  
           
            28 

Tyr Pro Phe Pro Gly 
 1               5 

 
           
             29  
             4  
             PRT  
             human  
             
               AMIDATION  
               (4)...(4)  
             
           
            29 

Tyr Pro Phe Phe 
 1 

 
           
             30  
             5  
             PRT  
             human  
           
            30 

Ala Pro Gly Pro Arg 
 1               5 

 
           
             31  
             5  
             PRT  
             human  
           
            31 

Val Pro Asp Pro Arg 
 1               5 

 
           
             32  
             42  
             PRT  
             human  
           
            32 

Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 
 1               5                  10                  15 

Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 
            20                  25                  30 

Lys Asn Asp Trp Lys His Asn Ile Thr Gln 
        35                  40 

 
           
             33  
             113  
             PRT  
             human  
           
            33 

Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr Glu Val Met Lys 
 1               5                  10                  15 

Cys Ile Val Glu Val Ile Ser Asp Thr Leu Ser Lys Pro Ser Pro Met 
            20                  25                  30 

Pro Val Ser Gln Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg Ile 
        35                  40                  45 

Leu Ser Ile Leu Arg His Gln Asn Leu Leu Lys Glu Leu Gln Asp Leu 
    50                  55                  60 

Ala Leu Gln Gly Ala Lys Glu Arg Ala His Gln Gln Lys Lys His Ser 
65                  70                  75                  80 

Gly Phe Glu Asp Glu Leu Ser Glu Val Leu Glu Asn Gln Ser Ser Gln 
                85                  90                  95 

Ala Glu Leu Lys Glu Ala Val Glu Glu Pro Ser Ser Lys Asp Val Met 
            100                 105                 110 

Glu 

 
           
             34  
             9  
             PRT  
             human  
           
            34 

Ser Ala Lys Glu Leu Arg Cys Gln Cys 
 1               5 

 
           
             35  
             14  
             PRT  
             human  
           
            35 

Gly Pro Val Ser Ala Val Leu Thr Glu Leu Arg Cys Thr Cys 
 1               5                  10 

 
           
             36  
             12  
             PRT  
             human  
           
            36 

Glu Ala Glu Glu Asp Gly Asp Leu Gln Cys Leu Cys 
 1               5                  10 

 
           
             37  
             11  
             PRT  
             human  
           
            37 

Val Pro Leu Ser Arg Thr Val Arg Cys Thr Cys 
 1               5                  10 

 
           
             38  
             11  
             PRT  
             human  
           
            38 

Thr Pro Val Val Arg Lys Gly Arg Cys Ser Cys 
 1               5                  10 

 
           
             39  
             11  
             PRT  
             human  
           
            39 

Lys Pro Val Ser Leu Ser Tyr Arg Cys Pro Cys 
 1               5                  10 

 
           
             40  
             11  
             PRT  
             human  
           
            40 

Ala Pro Leu Ala Thr Glu Leu Arg Cys Gln Cys 
 1               5                  10 

 
           
             41  
             11  
             PRT  
             human  
           
            41 

Phe Pro Met Phe Lys Lys Gly Arg Cys Leu Cys 
 1               5                  10 

 
           
             42  
             10  
             PRT  
             human  
           
            42 

Ser Pro Tyr Ser Ser Asp Thr Thr Pro Cys 
 1               5                  10 

 
           
             43  
             11  
             PRT  
             human  
           
            43 

Ala Pro Leu Ala Ala Asp Thr Pro Thr Ala Cys 
 1               5                  10 

 
           
             44  
             11  
             PRT  
             human  
           
            44 

Ala Pro Met Gly Ser Asp Pro Pro Thr Ala Cys 
 1               5                  10 

 
           
             45  
             11  
             PRT  
             human  
           
            45 

Gln Pro Asp Ala Ile Asn Ala Pro Val Thr Cys 
 1               5                  10 

 
           
             46  
             11  
             PRT  
             human  
           
            46 

Gln Pro Ser Asp Val Ser Ile Pro Ile Thr Cys 
 1               5                  10 

 
           
             47  
             10  
             PRT  
             human  
           
            47 

Gln Pro Val Gly Ile Asn Ser Thr Thr Cys 
 1               5                  10 

 
           
             48  
             11  
             PRT  
             human  
           
            48 

Gln Pro Asp Ala Leu Asp Val Pro Ser Thr Cys 
 1               5                  10 

 
           
             49  
             9  
             PRT  
             human  
           
            49 

Gly Pro Ala Ser Val Pro Thr Thr Cys 
 1               5 

 
           
             50  
             12  
             PRT  
             human  
           
            50 

Gly Pro Tyr Gly Ala Asn Met Glu Asp Ser Val Cys 
 1               5                  10