MODIFIED BIOLOGICAL PEPTIDES WITH INCREASED POTENCY

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: MODIFIED BIOLOGICAL PEPTIDES WITH INCREASED POTENCY FIELD OF THE INVENTION 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 ofthe peptide, or a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. BACKGROUND OF THE INVENTION 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 ofthe peptide so-modified. For example, it is known that substituting OH for a more hydrophobic group like -NEtj 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, wliich stresses the inefficacy 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. US 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. Biochemistry 2001, 40, pages 2860 to 2869 describes an hydrophobic glucagon-like peptide-1 (GLP-1) analog wherein hexenoic acid, a rigidified hydrophobic moiety is coupled to the GLP-1 peptide at the N-terminal ofthe 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 ofthe amino-acid composition of the natural molecule, which might have negative safety consequences for clinical applications, including the risks for immunogenicity and side effects. 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 increasing their half-life without changing the amino-acid sequence that would be clinically safe and acceptable. SUMMARY OF THE INVENTION In accordance with the present invention, there is now provided a peptide of formula X^-R λ wherein: - Rj is a peptide sequence which cannot be the GRF sequence when X represents a trans-3-hexenoyl group attached at N-terminal position ofthe peptide sequence; - each X can be identical or independent from the others and is selected from the following list constituted by conformationally rigid moieties bearing: 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 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; wherein, n is any digit between 1 to 5; X being defined as: i) a straight, substituted - o alkyl; ii) a branched, substituted -C JO alkyl; iii) a straight or branched, unsubstituted or substituted C C 10 alkene; iv) a straight or branched, unsubstituted or substituted C r C 10 alkyne; v) an unsubstituted or substituted, saturated or unsaturated C 3 -C 10 cycloalkyl or heterocycloalkyl wherein the heteroatom is O, S or N; vi) an unsubstituted or substituted C 5 -C 14 aryl or heteroaryl wherein the heteroatom is O, S or N; wherein the substituent in the definitions i) to vi) comprises one or more a) straight or branched - alkyl; b) straight or branched C C 6 alkene; c) straight or branched C[-C 6 alkyne; d) C 3 -C 10 cycloalkyl or heterocycloalkyl wherein at least 2 carbon atoms are optionally connected to the - Q alkyl, - Q alkene, -C K , alkyne, C 3 -Cι 0 cycloalkyl or heterocycloalkyl, and C 5 -Cι 4 aryl or heteroaryl; or e) C 5 -C 14 aryl or heteroaryl wherein at least 2 carbon atoms of the aryl or heteroaryl are optionally connected to the - o alkyl, C r C 10 alkene, C r C 10 alkyne, C 3 -C 10 cycloalkyl or heterocycloalkyl, and C 5 -C 14 aryl or heteroaryl; and any isomers thereof, including cis and trans configurations, epimers, enantiomers, diastereoisomers, and racemic mixtures. The term "aryl" includes phenyl, naphtyl 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, fiiranyl, imidazolyl, thiophanyl, pyrrolyl, quinolinyl, isoquinolinyl, pyrimidinyl, oxazolyl, thiazolyl, isothiazolyl, isooxazolyl, pyrazolyl, and the like. 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. 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, Endomoφhin-2, Procolipase, Enterostatin, gastric inhibitory peptide, Chromogranin A, Vasostatin I & II, Procalcitonin, ProNCT, ProCGRP, JX8 (monocyte-derived), GCP-2, PF4, IP-10, MIG, SDF-l , GRO-α, I-TAC, RANTES, LD78, MTP-lα, MCP-1, MCP-2, MCP-3, MCP-4, Eotaxin, MDC, and functional derivatives or fragments thereof. DETAILED DESCRIPTION OF THE INVENTION 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 Cysteine Cys Proline Pro Glutamic acid Glu Serine Ser Glutamine Gin Threonine Thr Glycine Gly Tryptophan Tip Histidine His Tyrosine Tyr Isoleucine He Valine Val 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. 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. The modified peptides of the present invention are prepared according to the following general method, well known in the art of solid phase synthesis. 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). 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. 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 ofthe C-terminal carboxylic acid. 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 lmin. 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 3min., drained again and finally another solution of piperidine 20% for lOmin. 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. 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. Coupling ofthe first Fmoc-amino acid to the Wang resin 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 15min 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. Coupling of each remaining amino acid on the growing peptide 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 DD?EA (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 ofthe reaction. 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-Asρ(OAl)-OH (PerSeptive Biosystems, catalog number : GEN911205) were carried out in the same way as for the Fmoc-amino acids as described above. Deprotection of allylic groups 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 x 0.05 / 0.05 eq) (palladium(II) bis-triphenylphosphine) was added to the mixture (Burger H., Kilion W., J Organometallics, 1969, 18:299). Then the (CH 3 CH 2 CH 2 ) 3 SnH (X mmol x 6 / 6eq ) (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). Coupling ofthe conformationally rigid acids and alkylamines The coupling of the conformationally rigid acids and amines to the side chains ofthe peptide-resin was conducted under the same conditions as those ofthe Fmoc-amino acids except that for these side chain modifications we used 10 equivalents ofthe rigid moieties and coupling reagent instead of 3. 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 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. Growth hormone releasing factor (GRF): 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 2S -Arg-Gln-Gln-Gly-Glu-Ser- Asn-Gin-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH 2 wherein, Xaa, is Tyr or His; Xaa, is Val or Ala: Xaa 8 is Asn or Ser; Xaa I3 is Val or He; Xaa 15 is Ala or Gly; Xaa 18 is Ser or Tyr; Xaa 24 is Gin or His; Xaa 25 is Asp or Glu; Xaa 27 is Met, He or Nle; and Xaa 28 is Ser or Asn. Somatostatin: Ala r Gly-Cys-Lys-Asn-Phe-Phe-T: Cys 14 -Ser-Xaa 12 -Phe-Thr-L Tys wherein, Xaa 12 is Tyr or Ser. Glucagon-like peptide 1 (7-37), (amide human (hGLP-1)): 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 ) Parathyroid hormone fragments (PTH 1-34): 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 2r Xaa 22 -Tφ-Leu-Xaa 25 -Xaa 26 -Lys-Leu-Gln-Asp-Val-His- Xaa 33 -Xaa 34 -NH 2 wherein, Xaa x is Ser or Ala; Xaa 5 is Ile or Met; Xaa 7 is Leu or Phe; Xaa 13 is Lys or Glu; Xaa 15 is Leu or Arg; Xaa 16 is Asn or Ala or Ser or His; Xaa is Ser of Thr; Xaa 18 is Met or Val or Leu; Xaa 21 is Val or met or Gin; Xaa 22 is Glu or Gin or Asp; Xaa 2S is Arg or Gin; Xaa 26 is Lys or Met; Xaa 33 is Asn or Ser; and Xaa 34 is Phe or Ala. Adrenocorticotropic hormone (ACTH): Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Tφ-Gly-Lys-Pro-Xaa I3 -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 wherein, Xaa 13 is Val or Met; Xaa x 5 is Lys or Arg; Xaa 20 is Val or He; Xaa 26 is Gly or Ser; Xaa 27 is Ala or Phe or Val; Xaa 28 is Glu or Gin; Xaa 29 is Asp or Asn or Glu; Xaa 31 is Ser or Thr; 5 Xaa 32 is Ala or Val or Ser; Xaa 34 is Ala or Asn or Gly; Xaa 35 is Phe or Met; Xaa 36 is Pro or Gly; Xaa 37 is Leu or Val or Pro; and o Xaa 39 is Phe or Val or Leu. Osteocalcin: Tyr-Leu-Xaa 52 -Xaa 53 -Xaa S4 -Leu-Gly-Ala-Pro-Xaa 59 -Pro-Tyr-Pro-Asp-Pro-Leu-Glu- Pro-Xaagg-Arg-Glu-Val-Cys-Glu-Leu-Asn-Pro-Xa^y-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 s wherein, Xaa 52 is Tyr or Asp or Asn; Xaa 53 is Gin or His or Asn; Xaa 54 is Tφ or Gly; Xaa 59 is Val or Ala; o Xaa 68 is Arg or Lys or His; Xaa 77 is Asp or Asn; Xaa 89 is Glu or Asp; Xaa 92 is Arg or Lys; Xaa 94 is Phe or He; and Xaa 97 is Pro or Thr. Calcitonin: Cys-Xaa 86 -Xaa 87 -Leu-Ser-Thr-Cys-Xaa 92 -Leu-Gly-Xaa 9S -Xaa 96 -Xaa 97 -Xaa 98 -Xaa 99 - ^aa^ Q -^ Q -^ ^ Q2 -^a Q3 -- aa^ - nr- aa QQ -_ aa 07 "-^ a 8 --?vaa Q9 - a^o--^^a^^j- wherein, Xaa 86 is Gly or Ser or Ala; Xaa 87 is Asn or Ser; Xaa 92 is Met or Val; Xaa 95 is Thr or Lys; Xaa 96 is Tyr or Leu; Xaa 97 is Thr or Ser; Xaa 98 is Gin or Lys; Xaa 99 is Asp or Glu; Xaa 100 is Phe or Leu; Xaa 101 is Asn or His; Xaa 102 is Lys or Asn; Xaa 103 is Phe or Leu; Xaa 104 is His or Gin; Xaa 106 is Phe or Tyr; Xaa 107 is Pro or Ser; Xaa 108 is Gin or Gly or Arg; Xaa 109 is Thr or He; Xaa 110 is Ala or Gly or Ser or Asp or Asn; Xaa ιn is He or Phe or Val or Thr; Xaa 113 is Val or Ala or Ser; Xaa 114 is Gly or Glu; and Xaa U5 is Ala or Thr. Corticotropin releasing factor: 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 wherein, Xaa 101 is Ala or Pro; and Xaa 102 is Arg or Gly. Dynorphin A: H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Tφ-Asp-Asn-Gln-OH β-Endorphin: H-Tyr-Gly-Gly-Phe-Met-Tlιr-Xaa 243 -Glu-Xaa 245 -Ser-Gln-Thr-Pro-Leu-Xaa 251 -Tlτr- Leu-Phe-Lys-Asn-Ala-Ile-Xaa 2 5 9 -Lys-Asn-Xaa 262 -Xaa 263 -Lys-Lys-Gly-Xaa 267 -OH wherein, Xaa 243 is Ser or Pro; Xaa 245 is Lys or Arg; Xaa 251 is Val or Met; Xaa 259 is He or Val; Xaa 262 is Ala or Thr or Ser or Val; Xaa 263 is Tyr or His; and Xaa 267 is Glu or Leu or Gin or His. Bi Gastrin-1: 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- Tφ-Met-Asp-Phe-NH 2 wherein, Xaa 59 is Glu or Gin; Xaa 62 is Pro or Leu; Xaa 64 is Gly or Asp; Xaa 65 is Pro or Ser; Xaa 66 is Pro or Gin; Xaa 67 is His or Gin; Xaa 68 is Leu or Met or Phe or Gin; Xaa 69 is Val or He; Xaa 72 is Pro or Leu; Xaa 73 is Ser or Ala; Xaa 76 is Gin or Glu; Xaa 77 is Gly or Arg; Xaa 79 is Tφ or Pro or Arg; Xaa 80 is Leu or Val or Met; Xaa 82 is Glu or Lys; and Xaa 85 is Glu or Ala. GLP-2: His-Ala-Asp-Gly-Ser-Phe-Xaa 152 -Xaa 153 -Xaa 154 -Xaaι 55 -Xaa 15 g-Xaaι S7 -Xaa 158 -Leu-Asp- ^aa j g j -- a ^g-Ai -- aa jg4 -_ a jg5 -s k .aa 2gg -ine-\.aa 2g - aa^g 9 - irp-_\.aai 7j -.Λ.aai 72 -.Λ.aa 2 - wherein, Xaa 152 is Ser or Thr; Xaa 153 is Asp or Ser; Xaa 154 is Glu or Asp; Xaa 155 is Met or Phe; Xaa 156 is Asn or Ser; Xaa 157 is Thr or Lys; Xaa 1S8 is He or Val or Ala; Xaa 161 is Asn or He or His or Ser; Xaa 162 is Leu or Lys; Xaa 64 is Ala or Thr; Xaa 6s is Arg or Gin or Lys; Xaa g 6 is Asp or Glu; Xaa 68 is He or Leu; Xa 69 is Asn or Asp; Xaa 71 is Leu or He; Xa 72 is He or Leu; Xa 73 is Gin or Asn or His; Xa 75 is Lys or Pro; Xaa 76 is He or Val; Xaa 77 is Thr or Lys; and Xaa 78 is Asp or Glu. Luteinizing hormone-releasing hormone: Xaa r His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH wherein, Xa j is pGlu, 5-oxoPro or Gin. Melanocyte Stimulating Hormone (MSH) : Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Tφ-Gly-Lys-Pro-Val-NH 2 Atrial Natriuretic Peptide: 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 wherein, Xaa 135 is Met or He; and Xaa 142 is Gly or Ser. Neuromedin B: H-Gly-Asn-Leu-Tφ-Ala-Thr-Gly-His-Phe-Met-NH 2 Human Neuropeptide Y: 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 Human Orexin A: 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 Human Peptide YY: 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 Human Secretin: 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 Vasoactive Intestinal peptide (VIP): 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 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-Tφ-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-Gln-Ala-Thr-Gln-Ile- Ala-Lys Cecropin B: Lys-Tφ-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 (XI -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-Tφ-Leu- Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp- Tφ-Lys-His-Asn- Ile-Thr-Gln Chromogranin A Vasostatin I Vasostatin π: Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr Glu Val Met Lys Cys He Val Glu Val He Ser Asp Thr Leu Ser Lys Pro Ser Pro Met Pro Val Ser Gin Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg He Leu Ser He Leu Arg His Gin Asn Leu Leu Lys Glu Leu Gin Asp Leu Ala Leu Gin Gly Ala Lys Glu Arg Ala His Gin Gin Lys Lys His Ser Gly Phe Glu Asp Glu Leu Ser Glu Val Leu Glu Asn Gln Ser Ser Gin Ala Glu Leu Lys Glu Ala Val Glu Glu Pro Ser Ser Lys Asp Val Met Glu Procalcitonin ProNCT ProCGRP Chemokine family: CXC-group: IL8(monocyte-derived): SerAlaLysGluLeuArgCysGlnCys... GCP-2: GlyProValSerAlaValLeuThrGluLeuArgCysThrCys... PF4: GluAlaGluGluAspGlyAspLeuGlnCysLeuCys... IP-10: ValProLeuSerArgThrValArgCCysThrCys... MIG: ThrProValValArgLysGlyArgCysSerCys... SDF-lα: LysProValSerLeuSerTyrArgCysProCys... GRO-α: AlaProLeuAlaTlirGluLeuArgCysGlnCys ... I-TAC: PheProMetPheLysLysGlyArgCysLeuCys... CC-group: RANTES: SerProTyrSerSerAspThrThrProCys... LD78: AlaProLeuAlaAlaAspThrProThrAlaCys... MIP-l : AlaProMetGlySerAspProProThrAlaCys... MCP-1: GlnProAspAlalleAsnAlaProValThrCys... MCP-2: GlnProSerAspValSerlleProIleThrCys... MCP-3: GlnProValGlylleTAsnSeerThrThrCys... MCP-4: GlnProAspAlaLeuAspValProSerTlirCys... Eotaxin: GlyProAlaSerValProThrThrCys... MDC: GlyProTyrGlyAlaAsnMetGluAspSerValCys... and functional derivatives or fragments thereof. The complete definition ofthe previously listed sequences are known inter alia from Mentiein, R (1999) Regul. Pept. 85:9-24 and from De Meester, I. Et al. (2000) Adv ExpMed Biol. 477:67-87. Those documents are incoφorated by reference to the present application. In a more preferred embodiment, the peptide is substituted with one or more conformationally rigid moieties. Preferred structures of the corhOrmationally rigid moieties comprise those with a double bond, a triple bond or a saturated or unsaturated ring. 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 puφoses of the present invention. Among the preferred modified peptides according to the present invention, are those wherein the peptide sequence is the sequence of a natural peptide. 25 26 27 CH 3 CH 2 C^≡C CH 2 COOH CH 3 CH2" -CH, - HP 30 31 38 39 42 43 60 61 63 wherein, R is hydrogen, CH 3 or CH 2 CH 3 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 10 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 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 13 Position conformationally rigid moieties Also preferred among the modified peptides according to the invention are those peptides wherein; - 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 ofthe peptide sequence; - 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 ofthe peptide. sequence; - 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 ofthe peptide sequence; - 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 ofthe peptide sequence; - 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 ofthe peptide sequence; - 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; - 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; 5 - the peptide sequence is Vasostatin H and at least one conformationally rigid moiety is coupled with said Vasostatin H peptide sequence via an amide or ester bond at different positions ofthe peptide sequence; - the peptide sequence is RANTES and at least one conformationally rigid moiety is coupled with said RANTES peptide sequence via an amide or o ester bond at different positions of the peptide sequence; - 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 ofthe peptide sequence. 5 In the modified peptites of the invention, the conformationally rigid moiety is preferably coupled with said peptide sequence via an amide bond at the N- terminal. The modified peptides according to the invention, wherein the o conformationally rigid moiety is the formula referenced 60 in the description, are of a particular interest. The modified peptides of the present invention can be a<iministered 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. In addition to the carboxy and amino groups present at the C- and N- terminals respectively ofthe 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. 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 Synthesis of GLP-1 analogs 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 13 hGLP-l (7-37) analogs synthesis 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 (0.70mmole/g) and five equivalents of reagents (lOOμm scale, amino acids concentration of 200mM), 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 ofthe hGLP-1 (7-37) are: - Peptide # 1 = (O-Tolylacetic acid-His 7 )-hGLP-l (7-37) [O-Tolylacetic acid (13) (10 equivalents per coupling; coupling time 45 min)] - Peptide # 2 = ((+,-)-cw-2-Ethylcyclopropylacetic acid -His 7 )-hGLP-l (7- 37) [(+,-)-cw-2-Ethylcyclopropylacetic acid (60) (7.5 equivalents per coupling: coupling time 60 min)]. 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). The synthesis of GLP-1 analogs is well known to the person skilled in the art and is further 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 incoφorated by reference. Biological assess of GLP-1 analogs Materials & Methods Oral Glucose Tolerance Test (OGTT) 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 gavage 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 5 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 0 are the mean ± SEM of 4 to 11 animals per group. Test articles 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, h a first set of experiments 5 (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). wt GLPl: hGLP(7-37) o Peptide #1 : (O-Tolylacetic acid-His 7 )-hGLP-l (7-37) Peptide #2: ((+,-)-cis-2-Ethylcyclopropylacetic acid-His 7 )-hGLP-l (7-37) Peptide #3: (Hexenoyl-trans-3-His 7 )-hGLP-l (7-37) Results and conclusions 5 Results are shown in Fig I(study A) and Fig.II (study B) 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 mMxl20 min), o illustrating the validity and reproducibility ofthe 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 inteφreted as a limitation in its potential clinical usefulness. In contrast, peptide 3 (study A, Fig.l) was able to completely abolish the glucose response, but only at the 10 ug dose (9 + 26 mMxl20 min). Suφrisingly, 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 mMxl20 min; 10 ug: 61 ± 64 mMxl20 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 11 EXAMPLE 2 PTH 1-34 analogs 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 EXAMPLE 3 Somatostatin analogs h 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 10 While the invention has been described in connection with specific l o 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 ofthe appended claims.

Claims: WHAT IS CLAIMED IS: 1. A peptide of formula wherein: - R j is a peptide sequence, a functional analog thereof or a fragment thereof; each X can be identical or independent from the others and is selected from the following list constituted by conformationally rigid moieties: i) a straight, substituted C r C 10 alkyl; ii) a branched, substituted Cj- o alkyl; iii) a straight or branched, unsubstituted or substituted -C JQ alkene; iv) a straight or branched, unsubstituted or substituted -C JQ alkyne; v) an unsubstituted or substituted, saturated or unsaturated C 3 -C 10 cycloalkyl or heterocycloalkyl wherein the heteroatom is O, S or N; vi) an unsubstituted or substituted C 5 -C 14 aryl or heteroaryl wherein the heteroatom is O, S or N; wherein the substituent in the definitions i) to vi) comprises one or more a) straight or branched - alkyl; b) straight or branched - alkene; c) straight or branched -Cg alkyne; d) C 3 -C 10 cycloalkyl or heterocycloalkyl wherein at least 2 carbon atoms are optionally connected to the C r C 10 alkyl, C r C 10 alkene, C r C 10 alkyne, C 3 -C 10 cycloalkyl or heterocycloalkyl, and C 5 -C 14 aryl or heteroaryl; or 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 r C 10 alkyl, C^C^ alkene, C r C 10 alkyne, C 3 -C 10 cycloalkyl or heterocycloalkyl, and C 5 -C 14 aryl or heteroaryl, said group X also comprising at least one group selected from: α) 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 β) 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; wherein, n is any digit between 1 to 5; and any isomers thereof, including cis and trans configurations, epimers, enantiomers, diastereoisomers, and racemic mixtures, the peptides defined in claim 1 of U.S. Patent No. 6,020,311 being excluded. 2. A peptide as claimed in claim 1 wherein 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 (PTH 1-34), Adrenocorticotropic hormone (ACTH), Osteocalcin, Calcitonin, Corticotropin releasing factor, Dynoφhin A, β-Endoφhin, 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 (V P), Antibiotic peptides (Magainin 1, Magainin 2, Cecropin A, and Cecropin B), Substance P (SP), Beta Casomoφhin-5, Endomoφhin-2, Procolipase, Enterostatin, gastric inhibitory peptide, Chromogranin A, Vasostatin I & π, Procalcitonin, ProNCT, CGRP (Calcitonin Gene Related Peptide), IL8 (monocyte-derived), GCP-2, PF4, IP-10, MIG, SDF-lα, GRO-α, I-TAC, RANTES, LD78, MlP-lα, MCP-1, MCP-2, MCP-3, MCP-4, Eotaxin, MDC, and functional analogs and derivatives or fragments thereof. 3. A peptide as claimed in claim 1 or 2 wherein the conformationally rigid moiety comprises at least a double bond, a triple bond or a saturated or unsaturated ring. 4. A peptide as claimed in any one of claims 1 to 3 wherein the conformationally rigid moiety comprises one or more of the structures of Formula 1 to 63 as-defined in the description. 5. A peptide as claimed in any one of claims 1 to 4 wherein the peptide sequence is selected from the group consisting of: Growth hormone releasing factor (GRF): Xaaj-Xaaj-Asp-Ala-Ile-Phe-Thr-Xaag-Ser-Tyr-Arg-Lys-Xaa^-Leu-Xaa^-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 • wherein, Xaa, is Tyr or His; Xaa 2 is Val or Ala; Xaa 8 is Asn or Ser; Xaa 13 is Val or He; Xaa I5 is Ala or Gly; Xaa ls is Ser or Tyr; Xaa^ is Gin or His; Xaa 25 is Asp or Glu; Xaa 27 is Met, He or Nle; and Xaa 28 is Ser or Asn; Somatostatin: AkvGly-Cys-Lys-Asn-Phe-Phe-T Cys 14 -Ser-Xaa 12 -Phe-Thr-L rys wherein, Xaa 12 is Tyr or Ser; Glucagon-like peptide 1 (7-37), (amide human (hGLP-1)): His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala- Lys-Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-Gly-OH(NH 2 ) Parathyroid hormone fragments (PTH 1-34): Xaa j -Val-Ser-Glu-Xaa j -Gln-Xaa y -Met-His-Asn-Leu-Gly-Xaa^-His-Xaa j s-Xaau- Xaa 17 -Xaa 18 -Glu-Arg-Xaa 21 -Xaa 22 -Tφ-Leu-Xaa 25 -Xaa 26 -Lys-Leu-Gln-Asp-Val-His- Xaa 33 -Xaa 34 -NH 2 wherein, X a j is Ser or Ala; Xaa 5 is Ile or Met; Xaa 7 is Leu or Phe; Xaa 13 is Lys or Glu; Xaa 15 is Leu or Arg; Xaa 16 is Asn or Ala or Ser or His; Xaa 17 is Ser of Thr; Xaa 18 is Met or Val or Leu; Xaa 21 is Val or met or Gin; Xaa 22 is Glu or Gin or Asp; Xaa 25 is Arg or Gin; Xaa 26 is Lys or Met; Xaa 33 is Asn or Ser; and Xaa 34 is Phe or Ala; Adrenocorticotropic hormone (ACTH): Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Tφ-Gly-Lys-Pro-Xaa 13 -Gly-Xaa 15 -Lys-Arg-Arg- Pro-Xaa 2o -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 wherein, Xaa 13 is Val or Met; Xaa 15 is Lys or Arg; Xaa 20 is Val or He; Xaa 26 is Gly or Ser; Xaa 27 is Ala or Phe or Val; Xaa 28 is Glu or Gin; Xaa 29 is Asp or Asn or Glu; Xaa 31 is Ser or Thr; Xaa 32 is Ala or Val or Ser; Xaa 34 is Ala or Asn or Gly; Xaa 35 is Phe or Met; Xaa 36 is Pro or Gly; Xaa 37 is Leu or Val or Pro; and Xaa 39 is Phe or Val or Leu; Osteocalcin: Tyr-Leu-Xaa 52 -Xaa 53 -Xaa 54 -Leu-Gly-Ala-Pro-Xaa S9 -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 wherein, Xaa 52 is Tyr or Asp or Asn; Xaa 53 is Gin or His or Asn; Xaa 54 is Trp or Gly; Xaa 59 is Val or Ala; Xaa 68 is Arg or Lys or His; Xaa 77 is Asp or Asn; Xaa 89 is Glu or Asp; Xaa 92 is Arg or Lys; Xaa 94 is Phe or He; and Xaa 97 is Pro or Thr; Calcitonin: Cys-Xaa 86 -Xaa 87 -Leu-Ser-Thr-Cys-Xaa 92 -Leu-Gly-Xaa 95 -Xaa 96 -Xaa 97 -Xaa 98 -Xaa 99 - ^aajQ-\.aajQ 2 -s.aa^Q 2 -- aajQ-- aajQ 4 - inr- aajQg- a jQ-^- aa^Qg- aajQg- aajjQ-Λ-aajjj- wherein, Xaa 86 is Gly or Ser or Ala; Xaa 87 is Asn or Ser; Xaa 92 is Met or Val; Xaa 95 is Thr or Lys; Xaa 96 is Tyr or Leu; Xaa 97 is Thr or Ser; Xaa 98 is Gin or Lys; Xaa 99 is Asp or Glu; Xaa 100 is Phe or Leu; Xaa 101 is Asn or His; Xaa 102 is Lys or Asn; Xaa 103 is Phe or Leu; Xaa 104 is His or Gin; Xaa 106 is Phe or Tyr; Xaa 107 is Pro or Ser; Xaa 108 is Gin or Gly or Arg; Xaa 109 is Thr or He; Xaa 110 is Ala or Gly or Ser or Asp or Asn; Xaa m is He or Phe or Val or Thr; Xaa 113 is Val or Ala or Ser; Xaa is Gly or Glu; and Xaa 115 is Ala or Thr; Corticotropin releasing factor: Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu- Glu-Met-Xaa I01 -Xaa I02 -Ala-Glu-Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys- Leu-Met-Glu-Ile-Ile-NH 2 wherein, . Xaa 101 is Ala or Pro; and Xaa 102 is Arg or Gly; Dynorphin A: H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Tφ-Asp-Asn-Gln-OH β-Endorphin: H-Tyr-Gly-Gly-Phe-Met-Thr-Xaa 243 -Glu-Xaa 245 -Ser-Gm-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 wherein, Xaa 243 is Ser or Pro; Xaa 245 is Lys or Arg; Xaa 251 is Val or Met; Xaa 259 is He or Val; Xaa 262 is Ala or Thr or Ser or Val; Xaa 263 is Tyr or His; and Xaa 267 is Glu or Leu or Gin or His; Big Gastrin-1: pXaajg-Leu-Gly-Xaa^-Gln-Xaa^-Xaags-Xaage-Xaa^-Xaagg-Xaagg-Ala-Asp-Xa^- Xaa 73 -Lys-Lys-Xaa 76 -Xaa 77 -Pro-Xaa 79 -Xaa 80 -Glu-Xaa 82 -Glu-Glu-Xaa 85 -Ala-Tyr-Gly- Tφ-Met-Asp-Phe-NH 2 wherein, Xaa 59 is Glu or Gin; Xaa 62 is Pro or Leu; Xaa 64 is Gly or Asp; Xaa 65 is Pro or Ser; ' Xaa 66 is Pro or Gin; Xaa 67 is His or Gin; Xaa 6S is Leu or Met or Phe or Gin; Xaa 69 is Val or He; Xaa 72 is Pro or Leu; Xaa 73 is Ser or Ala; Xaa 76 is Gin or Glu; Xaa 77 is Gly or Arg; Xaa 79 is Tφ or Pro or Arg; Xaa 80 is Leu or Val or Met; Xaa 82 is Glu or Lys; and Xaa 85 is Glu or Ala; GLP-2: His-Ala-Asp-Gly-Ser-Phe-Xaaι 52 -Xaa 153 -Xaa 154 -Xaai 55 -Xaa 156 -Xaa 157 -Xaa 158 -Leu-Asp- Xaa 1 g 1 -Xaa 162 -Ala-Xaa 1 g 4 -Xaa 1 g S -Xaa 1gg -Phe-Xaa 168 -Xaa 169 -Tφ-Xaa 171 -Xaa 172 -Xaa 173 - 1 nr--Λ.aaj 75 --Λ.aa^ g-_ .a j 77 --Λ. ^ g; wherein, Xaa 152 is Ser or Thr; Xaa 153 is Asp or Ser; Xaa 154 is Glu or Asp; Xaa 155 is Met or Phe; Xaa 156 is Asn or Ser; Xaa 157 is Thr or Lys; Xaa 158 is He or Val or Ala; Xaa 161 is Asn or He or His or Ser; .Xaa 162 is Leu or Lys; Xaa 164 is Ala or Thr; Xaaj 65 is Arg or Gin or Lys; Xaa 166 is Asp or Glu; Xaa 168 is He or Leu; Xaa 169 is Asn or Asp; Xaa 171 is Leu or He; Xaa 172 is He or Leu; Xaa 173 is Gin or Asn or His; Xaa 175 is Lys or Pro; Xaa 176 is He or Val; Xaa 177 is Thr or Lys; and Xaa 178 is Asp or Glu; Luteinizing hormone-releasing hormone: Xaa r His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH wherein, Xa j is pGlu, 5-oxoPro or Gin. Melanocyte Stimulating Hormone (MSH): Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Tφ-Gly-Lys-Pro-Val-NH 2 Atrial Natriuretic Peptide: H-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Xaa ]35 -Asp-Arg-Ile-Gly-Ala- Gln-Ser-Xaa 142 -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-OH wherein, Xaa 135 is Met or He; and Xaa 142 is Gly or Ser; Neuromedin B: H-Gly-Asn-Leu-Tφ-Ala-Tlιr-Gly-His-Phe-Met-NH 2 Human Neuropeptide Y: 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 Human Orexin A: 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 Human Peptide YY: 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 Human Secretin: 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 Vasoactive Intestinal peptide (VIP): 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 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-Tφ-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-Gln-Ala-Thr-Gln-Ile-Ala- Lys , Cecropin B: Lys-Tφ-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 (Xl-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-Tφ-Leu- Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Tφ-Lys- His-Asn- Ile-Thr-Gln Chromogranin A Vasostatin I Vasostatin II: Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr Glu Val Met Lys Cys He Val Glu Val He Ser Asp Thr Leu Ser Lys Pro Ser Pro Met Pro Val Ser Gin Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg He Leu Ser He Leu Arg His Gin Asn Leu Leu Lys Glu Leu Gin Asp Leu Ala Leu Gin Gly Ala Lys Glu Arg Ala His Gin Gin Lys Lys His Ser Gly Phe Glu Asp Glu Leu Ser Glu Val Leu Glu Asn Gin Ser Ser Gin Ala Glu Leu Lys Glu Ala Val Glu Glu Pro Ser Ser Lys Asp Val Met Glu Procalcitonin ProNCT ProCGRP Chemokine family: CXC-group: IL8(monocy te-derived) : SerAlaLysGluLeuArgCysGlnCys... GCP-2: GlyProValSerAlaValLeuThrGluLeuArgCysThrCys... PF4: GluAlaGluGluAspGlyAspLeuGlnCysLeuCys ... IP-10: ValProLeuSerArgThrValArgCCysThrCys... MIG: ThrProValValArgLysGlyArgCysSerCys... SDF-lα: LysProValSerLeuSerTyrArgCysProCys... GRO-α: AlaProLeuAlaThrGluLeuArgCysGlnCys... I-TAC: PheProMetPheLysLysGlyArgCysLeuCys... CC-group: RANTES: SerProTyrSerSerAspThrThrProCys... LD78: AlaProLeuAlaAlaAspThrProThrAlaCys... MlP-lα: AlaProMetGlySerAspProProTlirAlaCys... MCP-1: GlnProAspAlalleAsnAlaProValThrCys... MCP-2: GlnProSerAspValSerlleProIleThrCys... MCP-3: GlnProValGlylleTAsnSeerThrThrCys... MCP-4: GlnProAspAlaLeuAspValProSerThrCys... Eotaxin: GlyProAlaSerValProThrThrCys... MDC: GlyProTyrGlyAlaAsnMetGluAspSerValCys... and functional analogs and derivatives or fragments thereof. 6. A peptide according to claim 5 wherein the peptide sequence is the sequence of a natural peptide and functional analog or a fragment thereof or a clinically safe and acceptable derivative or analog thereof. 7. A peptide as claimed in claim 1 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 10 8. A peptide as claimed in claim 1 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 9. A peptide as claimed in claim 1 wherein said 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 13 Position conformationally rigid moieties 10. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 11. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 12. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 13. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 14. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 15. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 16. A peptide as claimed in claim 1 wherein said peptide sequence is Gastrin inhibitory Peptide and at least one conformationally rigid moiety is coupled with said Gastrin Inhibitory Peptide sequence via an amide or ester bond at different positions ofthe peptide sequence. 17. A peptide as claimed in claim 1 wherein said peptide sequence is Vasostatin H and at least one conformationally rigid moiety- is coupled with said Vasostatin H peptide sequence via an amide or ester bond at different positions of the peptide sequence. 18. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 19. A peptide as claimed in claim 1 wherein said 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 ofthe peptide sequence. 20. A peptide as in any one of claims 1 to 18, wherein said conformationally rigid moiety is coupled with said peptide sequence via an amide or ester bond at the N-terminal. 21. A peptide according to any one of claims 8 to 19, wherein the conformationally rigid moiety has the formula 60 referenced in the description. 22. A peptide according to claim 20, wherein the peptide sequence is GLP-1. 23. Use of the peptide according to claim 22 in the treatment of glucose intolerance associated or not with insuline resistance pathologies. 24. Use accordmg to claim 23 in the treatment of type H diabetes. 25. A peptide according to claim 1 wherein said peptide sequence is CGRP and at least one conformationally rigid moiety is coupled with said CGRP peptide sequence via an amide or ester bond at different positions ofthe peptide sequence.

Inventors: ABRIBAT THIERRY, GRAVEL DENIS, HABI ABDELKRIM, ABRIBAT, THIERRY, GRAVEL, DENIS, HABI, ABDELKRIM
Applicants: ABRIBAT THIERRY, GRAVEL DENIS, HABI ABDELKRIM, THERATECHNOLOGIES INC, ABRIBAT, THIERRY, GRAVEL, DENIS, HABI, ABDELKRIM, THERATECHNOLOGIES INC.
Application year: 2001
Main classification: C07K14
IPC codes: A61K38, A61P3, C07K7, C07K14