HEPCIDIN ANALOGUES AND USES THEREOF

• US 20160222076A1
• Filed: 03/17/2014
• Published: 08/04/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Portagonist Therapeutics Incorporated
• Inventors: Bourne, Gregory Thomas, Vink, Simone, Madala, Praveen, Tofteng Shelton, Anne Pernille, Fog, Jacob Ulrik, Smythe, Mark Leslie, Frederick, Brian T.
• Granted Patent: US 9,822,157 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The present invention relates, inter alia, to certain hepcidin peptide analogues, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.

Claims

1. A peptide having the following structural formula I′

2. The peptide according to claim 1, wherein R1′

is hydrogen, isovaleric acid, isobutyric acid or acetyl.

4. The peptide according to claim 1, wherein X′

is a peptide having formula Ib′

5. The peptide according to claim 1, wherein X′

is a peptide having formula Ic′

18. The peptide according to claim 1, wherein the peptide exhibits hepcidin activity.

19. The peptide according to claim 1, wherein the peptide binds ferroportin.

20. A pharmaceutical composition which comprises at least one peptide according to claim 1 and a pharmaceutically acceptable carrier or excipient.

21. A method of binding a ferroportin or inducing ferroportin internalization and degradation which comprises contacting the ferroportin with the composition according to claim 20.

22. A method of treating a disease of iron metabolism in a subject which comprises administering the composition according to claim 20 to the subject.

3. (canceled)

6-17. -17. (canceled)

23-30. -30. (canceled)

31. A peptide having the following structural formula I″

32. The peptide of claim 31, wherein said compound is PEGylated on R¹″

, X″

, or Y″

.

33. The peptide of claim 31, wherein said compound of comprises two or more cysteine residues, at least two of said cysteine residues being linked via a disulfide bond.

34. The peptide of claim 31, wherein R¹″

is hydrogen, isovaleric acid, isobutyric acid or acetyl.

35. The peptide of claim 31,

wherein

X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;

X2 is Thr, Ala, or D-Thr;

X3 is His, Lys, D-His or Lys;

X4 is Phe, Ala, or Dpa;

X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;

X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;

X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;

X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;

X9 is Phe or bhPhe; and

X10 is Lys or absent.

36. The peptide of claim 31, wherein X″

is a peptide sequence having the formula Ib″

instead of Ia″

,

37. The peptide of claim 31, wherein X″

is a peptide sequence having the formula Ic″

instead of Ia″

,

40. The peptide of claim 31, wherein the peptide of formula I″

comprises at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten Y″

residues.

44. The peptide of claim 31, wherein the peptide exhibits hepcidin activity or binds ferroportin.

46. A pharmaceutical composition comprising at least one peptide according to claim 31 and a pharmaceutically acceptable carrier of excipient.

47. A method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with the composition according to claim 46.

48. A method for treating a disease of iron metabolism in a subject comprising administering the composition according to claim 46 to the subject.

38-39. -39. (canceled)

41-43. -43. (canceled)

45. (canceled)

49-56. -56. (canceled)