Treatments of gastrointestinal disorders

1. A method for treating a gastrointestinal disorder comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Cys 5 Xaa 6 Xaa 7 Xaa 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Xaa 14 Gly 15 Xaa 16 Xaa 17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; wherein

Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, γ-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), α-aminopimelic acid (Apm), or is absent;

Xaa 2 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa 3 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa 4 is Cys or D-Cys;

Xaa 6 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;

Xaa 7 is Tyr, Leu, Phe or Ile;

Xaa 8 is Cys or D-Cys;

Xaa 14 is Thr, Ala or Phe;

Xaa 16 is Cys or D-Cys; and

Xaa 17 is Tyr, D-Tyr, or is absent;

wherein:

if Xaa 1 is present, Xaa 1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;

if Xaa 1 is absent and Xaa 2 is present, then Xaa 2 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; or

if both Xaa 1 and Xaa 2 are absent, then Xaa 3 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

2. The method according to claim 1 , wherein

Xaa 2 is Asp, Glu, or absent;

Xaa 3 is Asp, Glu, or absent;

Xaa 7 is Tyr or Leu;

Xaa 14 is Thr; and

Xaa 17 is Tyr or is absent.

3. The method according to claim 1 , wherein Xaa 1 is Asp, D-Asp, Glu, D-Glu, or absent; and Xaa 6 is P-Ser or P-Thr.

4. The method according to claim 3 , wherein Xaa 6 is P-Ser.

5. The method according to claim 1 , wherein Xaa 1 , Xaa 2 and Xaa 3 are absent.

6. The method according to claim 1 , wherein said peptide comprises the amino acid sequence

Cys 4 Cys 5 P-Ser 6 Xaa 7 Cys g Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Thr 14 Gly 15 Cys 16 Xaa 17 (SEQ ID NO: 15),

wherein Xaa 7 is Tyr or Leu, and Xaa 17 is Tyr, D-Tyr, or is absent.

7. The method according to claim 1 , wherein said peptide comprises the amino acid sequence:

(SEQ ID NO: 2)

Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr;

(SEQ ID NO: 3)

Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys;

(SEQ ID NO: 4)

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr;

(SEQ ID NO: 5)

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys;

(SEQ ID NO: 6)

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr;

(SEQ ID NO: 7)

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys;

(SEQ ID NO: 8)

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr;

or

(SEQ ID NO: 9)

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys.

8. The method according to claim 1 , wherein the peptide comprises the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7).

9. The method according to claim 1 , wherein said peptide or pharmaceutically acceptable salt thereof is isolated.

10. The method according to claim 9 , wherein said peptide or pharmaceutically acceptable salt thereof is purified.

11. The method according to claim 1 , wherein said gastrointestinal disorder is gastroparesis, post-operative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), celiac disease, mucositis, or a duodenal or stomach ulcer.

12. The method according to claim 11 , wherein the functional gastroduodenal disorder is functional dyspepsia, a belching disorder, a nausea or vomiting disorder or rumination syndrome.

13. A method for treating a gastrointestinal disorder comprising administering a pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to claim 1 .

14. The method according to claim 13 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and one or more agents selected from (i) a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + and Al 3+ , and (ii) a sterically hindered primary amine.

15. The method according to claim 14 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .

16. The method according to claim 14 , wherein said agent is a sterically hindered primary amine.

17. The method according to claim 16 , wherein the sterically hindered primary amine is an amino acid.

18. The method according to claim 12 , wherein the pharmaceutical composition further comprises an antioxidant selected from BHA, vitamin E and propyl gallate.

19. The method according to claim 13 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable binder or additive selected from polyvinyl alcohol, Polyvinylpyrrolidone (povidone), a starch, maltodextrin and a cellulose ether.

20. The method according to claim 13 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable filler selected from cellulose, isomalt, mannitol, lactose and dibasic calcium phosphate.

21. The method according to claim 13 , wherein the pharmaceutical composition comprises a peptide or pharmaceutically acceptable salt thereof comprising the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7).

22. The method according to claim 13 , wherein said gastrointestinal disorder is gastroparesis, post-operative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), celiac disease, mucositis, or a duodenal or stomach ulcer.

23. The method according to claim 22 , wherein the functional gastroduodenal disorder is functional dyspepsia, a belching disorder, a nausea or vomiting disorder or rumination syndrome.

24. The method according to claim 11 , wherein the gastrointestinal disorder is gastroparesis.

25. The method according to claim 24 , wherein the gastroparesis is idiopathic gastroparesis.

26. The method according to claim 24 , wherein the gastroparesis is diabetic gastroparesis.

27. The method according to claim 24 , wherein the gastroparesis is post-surgical gastroparesis.

28. The method according to claim 12 , wherein the functional gastroduodenal disorder is functional dyspepsia.

29. The method according to claim 28 , wherein the functional dyspepsia is postprandial distress syndrome or epigastric pain syndrome.

30. The method according to claim 22 , wherein the gastrointestinal disorder is gastroparesis.

31. The method according to claim 30 , wherein the gastroparesis is idiopathic gastroparesis.

32. The method according to claim 30 , wherein the gastroparesis is diabetic gastroparesis.

33. The method according to claim 30 , wherein the gastroparesis is post-surgical gastroparesis.

34. The method according to claim 23 , wherein the functional gastroduodenal disorder is functional dyspepsia.

35. The method according to claim 34 , wherein the functional dyspepsia is postprandial distress syndrome or epigastric pain syndrome.