Treatments for gastrointestinal disorders
The present invention provides peptides that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmaceutical compositions include oral dosage forms.
1. 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 peptide or pharmaceutically acceptable salt thereof 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 peptide or pharmaceutically acceptable salt thereof 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 peptide or pharmaceutically acceptable salt thereof according to claim 3 , wherein Xaa 6 is P-Ser.
5. The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein Xaa 1 , Xaa 2 and Xaa 3 are absent.
6. The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide comprises the amino acid sequence
Cys 4 Cys 5 P-Ser 6 Xaa 7 Cys 8 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 peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide comprises the amino acid sequence:
Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:2);
Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:3);
Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);
Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:5);
Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:6);
Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7);
Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:8); or
Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:9).
8. The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide comprises no more than 50, 40, 30 or 20 amino acids.
9. The peptide or pharmaceutically acceptable salt thereof according to claim 8 , wherein said peptide comprises no more than 19, 18, 17, 16, 15 or 14 amino acids.
10. A peptide consisting of 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.
11. The peptide or pharmaceutically acceptable salt thereof according to claim 10 , 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.
12. The peptide or pharmaceutically acceptable salt thereof according to claim 10 , wherein Xaa 1 is Asp, D-Asp, Glu, D-Glu or absent; and Xaa 6 is P-Ser or P-Thr.
13. The peptide or pharmaceutically acceptable salt thereof according to claim 12 , wherein Xaa 6 is P-Ser.
14. The peptide or pharmaceutically acceptable salt thereof according to claim 10 , wherein Xaa 1 , Xaa 2 and Xaa 3 are absent.
15. The peptide or pharmaceutically acceptable salt thereof according to claim 10 , wherein said peptide comprises the amino acid sequence
Cys 4 Cys 5 P-Ser 6 Xaa 7 Cys 8 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.
16. The peptide or pharmaceutically acceptable salt thereof according to claim 10 , wherein said peptide consists of the amino acid sequence:
Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:2);
Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:3);
Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);
Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:5);
Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:6);
Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7);
Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:8); or
Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:9).
17. The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide or pharmaceutically acceptable salt thereof is isolated.
18. The peptide or pharmaceutically acceptable salt thereof according to claim 17 , wherein said peptide or pharmaceutically acceptable salt thereof is purified.
19. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to claim 1 .
20. The pharmaceutical composition according to claim 19 further comprising 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.
21. The pharmaceutical composition according to claim 20 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .
22. The pharmaceutical composition according to claim 20 , wherein said agent is a sterically hindered primary amine.
23. The pharmaceutical composition according to claim 22 , wherein the sterically hindered primary amine is an amino acid.
24. The pharmaceutical composition according to claim 19 , further comprising an antioxidant selected from BHA, vitamin E and propyl gallate.
25. The pharmaceutical composition according to claim 19 , further comprising a pharmaceutically acceptable binder or additive selected from polyvinyl alcohol, Polyvinylpyrrolidone (povidone), a starch, maltodextrin and a cellulose ether.
26. The pharmaceutical composition according to claim 19 , further comprising a pharmaceutically acceptable filler selected from cellulose, isomalt, mannitol, lactose and dibasic calcium phosphate.
27. A peptide or a pharmaceutically acceptable salt thereof, 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).
28. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, 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).
29. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7).
30. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7).