Hepcidin and mini-hepcidin analogues and uses thereof

Patent metadata

Field	Value
Publication number	US-2017313754-A1
Application number	US-201515321124-A
Country	US
Kind code	A1
Filing date	Jun 29, 2015
Priority date	Jun 27, 2014
Publication date	Nov 2, 2017
Grant date	—

Abstract

The present invention provides novel hepcidin analogues, and related methods of using these hepcidin analogues to treat or prevent a variety of diseases and disorders, including iron overload diseases such as hereditary hemochromatosis, iron-loading anemias, and other conditions and disorders described herein.

First claim

1 . A hepcidin analogue having the structure of Formula I:
SEQ ID NO:1 R 1 -X-Y-R 2   (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; R 2 is OH or NH 2 ; X is a peptide sequence having the formula Ia:
SEQ ID NO:2
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10  (Ia)

wherein X1 is Asp, Ser, Glu, Ida, pGlu, bhAsp, D-Asp or absent; X2 is Thr, Ser, Lys, Glu, Pro, Ala or absent; X3 is His, Ala, or Glu; X4 is Phe, Ile or Dpa; X5 is Pro, bhPro, Val, Glu, Sarc or Gly; X6 is Cys or (D)-Cys; X7 is absent or any amino acid except Ile, Cys or (D)-Cys; X8 is absent or any amino acid except Cys or (D)-Cys; X9 is Phe, Ala, Ile, Thr, Tyr, Lys, Arg, bhPhe, D-Phe or absent; and X10 is Lys, Phe or absent; and Y is absent or present; provided that if Y is present, Y is a peptide having the formula Im:
SEQ ID NO:3
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12  (Im)

wherein Y1 is Gly, PEG3, Sarc, Lys, Glu, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent; Y2 is Pro, Ala, Cys, Gly or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Glu, Tyr or absent; Y5 is Lys, Met, Ser, Arg, Ala or absent; Y6 is Gly, Sarc, Glu, Lys, Arg, Ser, Lys, Ile, Ala, Pro, Val or absent; Y7 is Trp, Lys, Gly, Ala Ile, Val or absent; Y8 is Val, Trp, His, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent; Y9 is Val, Asp, Asn, Cys, Tyr or absent; Y10 is Cys, Met, Lys, Arg, Tyr or absent; Y11 is Arg, Met, Cys, Lys or absent; and Y12 is Arg, Lys, Ala or absent.

2 . The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein X is a peptide sequence having the formula Ib:
SEQ ID NO:18 X1-X2-X3-X4-X5-X6-X7-X8-X9-X10  (Ib)

wherein
X1 is Asp, Glu, Ida, pGlu, bhAsp, D-Asp or absent;
X2 is Thr, Ser, Lys, Glu, Pro, Ala or absent;
X3 is His, Ala, or Glu;
X4 is Phe, Ile or Dpa;
X5 is Pro, bhPro, Sarc or Gly;
X6 is Cys;
X7 is absent or any amino acid except Ile, Cys or (D)-Cys;
X8 is absent or any amino acid except Cys or (D)-Cys;
X9 is Phe, Ile, Tyr, bhPhe or D-Phe or absent; and
X10 is Lys, Phe or absent; and
wherein Y is absent or present, provided that if Y is present, Y is a peptide having the formula In:
SEQ ID NO:19
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12  (In)

wherein
Y1 is Gly, PEG3, Sarc, Lys, Glu, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, or absent;
Y4 is Ser, Arg, Glu or absent;
Y5 is Lys, Ser, Met, Arg, Ala or absent;
Y6 is Gly, Sarc, Glu, Leu, Phe, His or absent;
Y7 is Trp, N-Methyl Trp, Lys, Thr, His, Gly, Ala, Ile, Val or absent;
Y8 is Val, Trp, Ala, Asn, Glu or absent;
Y9 is Val, Ala, Asn, Asp, Cys or absent;
Y10 is Cys, (D)Cys, Glu or absent;
Y11 is Tyr, Met or absent; and
Y12 is Trp or absent.

3 . The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the hepcidin analogue comprises an amino acid sequence or a structure shown in Table 2.

4 . A hepcidin analogue having the structure of Formula II:
SEQ ID NO:4 R 1 -X-Y-R 2   (II)
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; R 2 is OH or NH 2 ; X is a peptide sequence having the formula IIa:
SEQ ID NO:5 SEQ ID NO:5
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10  (IIa)

wherein X1 is Asp, Glu or Ida; X2 is Thr, Ser or absent; X3 is His; X4 is Phe or Dpa; X5 is Pro, bhPro, Sarc or Gly; X6 is Cys or (D)-Cys; X7 is Arg, Glu, Phe, Gln, Leu, Val, Lys, Ile, Ala, Ser, Dapa or absent; X8 is Ile, Arg, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, Dapa or absent; X9 is Phe, Tyr, bhPhe, D-Phe or absent; and X10 is Lys, Phe or absent; and wherein Y is absent or present, provided that if Y is present, Y is a peptide having the formula IIm:
SEQ ID NO:6
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12  (IIm)

wherein Y1 is Gly, Sarc, Lys, Glu or absent; Y2 is Pro, Ala, Gly or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala or absent; Y4 is Ser, Arg, Glu or absent; Y5 is Lys, Ser, Met, Arg, Ala or absent; Y6 is Gly, Sarc, Glu, Leu, Phe, His or absent; Y7 is Trp, NMe-Trp, Lys, Thr, His, Gly, Ala Ile, Val or absent; Y8 is Val, Trp, Ala, Asn, Glu or absent; Y9 is Cys; Y10 is absent; Y11 is absent; and Y12 is absent.

5 . The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 4 , wherein the hepcidin analogue comprises an amino acid sequence or a structure shown in Table 3.

6 . A dimer or a pharmaceutically acceptable salt or solvate thereof, comprising two hepcidin analogues, each hepcidin analogue having the structure of Formula I, the structure of Formula II, the structure of Formula III, the structure of Formula IV, the structure of Formula V, the structure of Formula VI, or a sequence or structure shown in any one of Tables 2-4 and 6-8, or 10-12, provided that when the dimer comprises a hepcidin analogue having the structure of Formula III, Formula IV, Formula V, or Formula VI, the two hepcidin analogues are linked via a lysine linker.

7 . The dimer or pharmaceutically acceptable salt or solvate thereof of claim 6 , wherein one or both hepcidin analogue has the structure of Formula I or the structure of Formula II.

8 . (canceled)

9 . The dimer or pharmaceutically acceptable salt or solvate thereof of claim 6 , wherein one or both hepcidin analogue has the Formula III:
SEQ ID NO:7 R 1 -X-Y-R 2   (III)
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions thereof, alone or as spacers of any of the foregoing; R 2 is —NH 2 or —OH; X is a peptide sequence having the formula (IIIa)
SEQ ID NO:8
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10  (IIIa)

wherein X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent; X2 is Thr, Ala, Aib, D-Thr, Arg or absent; X3 is His, Lys, Ala, or D-His; X4 is Phe, Ala, Dpa or bhPhe; X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent; X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala; X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys; X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or Dapa; X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and X10 is Lys, Phe or absent; and Y is absent or present, and when present, Y is a peptide having the formula (IIIm)
SEQ ID NO:9
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15  (IIIm)

wherein Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent; Y2 is Pro, Ala, Cys, Gly or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent; Y5 is Lys, Met, Arg, Ala or absent; Y6 is Gly, Ser, Lys, Ile, Arg, Ala, Pro, Val or absent; Y7 is Trp, Lys, Gly, Ala, Ile, Val or absent; Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent; Y9 is Cys, Tyr or absent; Y10 is Met, Lys, Arg, Tyr or absent; Y11 is Arg, Met, Cys, Lys or absent; Y12 is Arg, Lys, Ala or absent; Y13 is Arg, Cys, Lys, Val or absent; Y14 is Arg, Lys, Pro, Cys, Thr or absent; and Y15 is Thr, Arg or

Assignees

• Protagonist Therapeutics Inc
• Protagonist Therapeutics Inc

Inventors

• Bourne Gregory Thomas
• Smythe Mark Leslie
• Frederick Brian Troy
• Vink Simone

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K38/00

  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 title

• C07K14/575 Primary

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · CPC title