INHIBITION OF GLIADIN PEPTIDES

• US 20180134750A1
• Filed: 01/02/2018
• Published: 05/17/2018
• Est. Priority Date: 05/06/2008
• Status: Active Grant

• Current Assignee: Alba Therapeutics Corporation (Teva Pharmaceutical Industries Limited)
• Original Assignee: Alba Therapeutics Corporation (Teva Pharmaceutical Industries Limited)
• Inventors: Alkan, Sefik, Tamiz, Amir, Kitchens, Kelly Marie, Durai, Malarvizhi, Poloso, Neil, Carrasco, Rosa A.
• Granted Patent: US 10,526,372 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 5/0804 and aliphatic
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0815 with the first amino acid being basic
• CPC Class Codes: C07K 5/0817 the first amino acid being Arg
• CPC Class Codes: C07K 5/0819 with the first amino acid being acidic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids

Abstract

Novel compounds and methods for the inhibition of biological barrier permeability and for the inhibition of peptide translocation across biological barriers are identified. Assays for determining modulators of biological barrier permeability and for peptide translocation across biological barriers are provided. Methods for treating diseases relating to aberrant biological barrier permeability and peptide translocation across biological barriers are provided. Such diseases include celiac disease, necrotizing enterocolitis, diabetes, cancer, inflammatory bowel diseases, asthma, COPD, excessive or undesirable immune response, gluten sensitivity, gluten allergy, food allergy, rheumatoid arthritis, multiple sclerosis, immune-mediated or type 1 diabetes mellitus, systemic lupus erythematosus, psoriasis, scleroderma and autoimmune thyroid diseases.

Claims

1. A peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162, wherein said peptide permeability inhibitor inhibits translocation of a gliadin-derived peptide across a biological barrier.

2. The peptide of claim 1, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

3. The peptide of claim 1, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

4. A method of inhibiting gliadin-derived peptide translocation across a biological barrier comprising contacting said barrier with a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

5. The method of claim 4, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

6. The method of claim 4, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

7. A composition for inhibiting gliadin-derived peptide translocation across a biological barrier, wherein said composition comprises a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

8. The composition of claim 7, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

9. The composition of claim 7, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

10. A method for inhibiting gliadin-derived peptide translocation across a biological barrier comprising administering to a subject in need thereof the composition of claim 7 in an amount sufficient to inhibit said gliadin-derived peptide translocation.

11. The method of claim 10, wherein the composition is administered in conjunction with an additional therapeutic agent.

12. The method of claim 11, wherein the composition and the additional therapeutic agent are administered simultaneously.

13. The method of claim 11, wherein the composition and the additional therapeutic agent are not administered simultaneously.

14. The method of claim 11, wherein the composition further comprises the additional therapeutic agent.

15. The method of claim 11, wherein the additional therapeutic agent is selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.

16. A peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162, wherein said peptide inhibits a gliadin-induced increase in biological barrier permeability.

17. The peptide of claim 16, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

18. The peptide of claim 16, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

19. A method of inhibiting a gliadin-induced increase in biological barrier permeability comprising contacting said barrier with a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

20. The method of claim 19, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

21. The method of claim 19, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

22. A composition for inhibiting a gliadin-induced increase in biological barrier permeability, wherein said composition comprises a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

23. The composition of claim 22, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

24. The composition of claim 22, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

25. A method for inhibiting a gliadin-induced increase in biological barrier permeability comprising administering to a subject in need thereof the composition of claim 22 in an amount sufficient to inhibit said increase in biological barrier permeability.

26. The method of claim 25, wherein the composition is administered in conjunction with an additional therapeutic agent.

27. The method of claim 26, wherein the composition and the additional therapeutic agent are administered simultaneously.

28. The method of claim 26, wherein the composition and the additional therapeutic agent are not administered simultaneously.

29. The method of claim 26, wherein the composition further comprises the additional therapeutic agent.

30. The method of claim 26, wherein the additional therapeutic agent is selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.

31. A method of treating a patient with celiac disease, comprising administering to the patient a composition comprising a peptide that inhibits translocation of a gliadin-derived peptide across a biological barrier.

32. The method of claim 31, wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

33. The method of claim 32, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

34. The method of claim 32, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

35. The method of claim 31, wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.

36. A method of treating a patient with diabetes, comprising administering to the patient a composition comprising a peptide that inhibits a gliadin-induced increase in biological barrier permeability.

37. The method of claim 36, wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

38. The method of claim 37, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

39. The method of claim 37, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

40. The method of claim 36, wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.

41. A method of treating a patient with dermatitis herpetiformis, comprising administering to the patient a composition comprising a peptide that inhibits translocation of a gliadin-derived peptide across a biological barrier.

42. The method of claim 41, wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-162.

43. The method of claim 42, wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs:

15, 24 and 25.

44. The method of claim 42, wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162.

45. The method of claim 41, wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.