IP Library › Patent Application 15720333
Patent Application
App. No. 15/720,333

HEPCIDIN ANALOGUES AND USES THEREOF

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Quick Facts
Patent No.
US None
App. No.
15/720,333
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 (331)

1 - 56 . (canceled)

57 . A peptide having the following structural formula I′

R1′-X′-Y′-R2′  (I′) (SEQ ID NO:21)

or a pharmaceutically acceptable salt thereof,

wherein

R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu;

R2′ is —NH 2 or —OH;

X′ is a peptide sequence having the formula Ia′

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10   (Ia′) (SEQ ID NO:13)

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, Dpa or D-Phe;

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, Phe or absent;

wherein if Y′ is absent, X7 is Ile; and

Y′ is a peptide sequence having the formula IIa′

Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15   (IIa′) (SEQ ID NO:16)

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, 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 absent;

wherein the peptide of formula I′ comprises at least two cysteine residues.

58 . The peptide or pharmaceutically acceptable salt thereof of claim 57 , wherein the peptide comprises two cysteine residues linked via a disulfide bond.

59 . The peptide or pharmaceutically acceptable salt thereof of claim 57 , wherein the peptide is PEGylated on R1′, X′, or Y′.

60 . The peptide or pharmaceutically acceptable salt thereof of claim 57 , wherein a side chain of an amino acid of the peptide is conjugated to a lipophilic substituent or a polymeric moiety.

61 . The peptide or pharmaceutically acceptable salt thereof according to claim 57 , wherein R1′ is hydrogen, isovaleric acid, isobutyric acid or acetyl.

62 . The peptide or pharmaceutically acceptable salt thereof according to claim 57 , wherein X′ is a peptide sequence having formula Ib′

X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10   (Ib′) (SEQ ID NO:14)

wherein

X1 is Asp, Ida, pGlu, bhAsp or absent;

X4 is Phe or Dpa;

X5 is Pro or bhPro;

X6 is Ile, Cys or Arg;

X7 is Cys, Ile, Leu or Val;

X8 is Ile, Lys, Glu, Phe, Gln or Arg; and

X10 is Lys or absent.

63 . The peptide or pharmaceutically acceptable salt thereof according to claim 57 , wherein X′ is a peptide sequence having formula Ic′

X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10   (Ic′) (SEQ ID NO:15)

wherein

X1 is Asp, Ida, pGlu, bhAsp or absent;

X4 is Phe or Dpa;

X5 is Pro or bhPro;

X8 is Ile, Lys, Glu, Phe, Gln or Arg; and

X10 is Lys or absent.

64 . The peptide or pharmaceutically acceptable salt thereof according to claim 63 , wherein X1 is Asp, X4 is Phe, and X5 is Pro.

65 . The peptide or pharmaceutically acceptable salt thereof of claim 57 , wherein the peptide comprises one of the following sequences:

(SEQ ID NO: 29)

DTHFPICIFGPRSKGWVC;

(SEQ ID NO: 38)

DTHFPCIIFGPRSKGWVCK;

(SEQ ID NO: 128)

DTHFPCIIFEPRSKGWVCK;

(SEQ ID NO: 164)

DTHFPCIIFGPRSKGWACK;

(SEQ ID NO: 168)

DTHFPCIIFGPRSKGWVCKK;

(SEQ ID NO: 57

DTHFPCIIFVCHRPKGCYRRVCR;

(SEQ ID NO: 125)

DTHFPCIKFGPRSKGWVCK;

(SEQ ID NO: 173)

DTHFPCIKFKPRSKGWVCK;

(SEQ ID NO: 106)

DTHFPCIIFGPRSRGWVCK;

(SEQ ID NO: 135)

DTHFPCIKFGPKSKGWVCK;

(SEQ ID NO: 207)

DTHFPCIKFEPRSKGCK;

(SEQ ID NO: 265)

DTHFPCIKFEPKSKGWECK;

(SEQ ID NO: 245)

DTHFPCIKFEPRSKKCK;

(SEQ ID NO: 247)

DTHFPCIKFEPRSKGCKK;

(SEQ ID NO: 249)

DTHFPCIKFKPRSKGCK;

or

(SEQ ID NO: 250)

DTHFPCIKFEPKSKGCK.

66 . The peptide or pharmaceutically acceptable salt thereof of claim 65 , comprising one of the following structures:

(SEQ ID NO: 29)

Isovaleric acid-DTHFPICIFGPRSKGWVC-NH 2 ;

(SEQ ID NO: 38)

Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 128)

Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 ;

(SEQ ID NO: 164)

Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH 2 ;

(SEQ ID NO: 168)

Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH 2 ;

(SEQ ID NO: 57)

Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH 2 ;

(SEQ ID NO: 172)

Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 173)

Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 ;

(SEQ ID NO: 199)

Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVC-NH 2 ;

(SEQ ID NO: 200)

Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVC-NH 2 ;

(SEQ ID NO: 201)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 ;

(SEQ ID NO: 202)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH 2 ;

(SEQ ID NO: 203)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH 2 ;

(SEQ ID NO: 183)

Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 217)

Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH 2 ;

(SEQ ID NO: 219)

Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 ;

(SEQ ID NO: 220)

Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH 2 ;

(SEQ ID NO: 221)

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))NH 2 ;

(SEQ ID NO: 222)

Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-

NH 2 ;

(SEQ ID NO: 223)

Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-

NH 2 ;

(SEQ ID NO: 224)

Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-

NH 2 ;

(SEQ ID NO: 225)

Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-

NH 2 ;

(SEQ ID NO: 226)

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-

NH 2 ;

(SEQ ID NO: 176)

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 ;

(SEQ ID NO: 241)

Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-

NH 2 ;

(SEQ ID NO: 242)

Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-

NH 2 ;

(SEQ ID NO: 243)

Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-

NH 2 ;

(SEQ ID NO: 265)

Isovaleric acid-

DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-NH 2 ;

(SEQ ID NO: 244)

Isovaleric acid-

DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 ;

(SEQ ID NO: 245)

Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-

NH 2 ;

(SEQ ID NO: 246)

Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-

NH 2 ;

(SEQ ID NO: 248)

Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-

NH 2 ;

(SEQ ID NO: 249)

Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-

NH 2 ;

(SEQ ID NO: 250)

Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-

NH 2 ;

(SEQ ID NO: 251)

Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-

NH 2 ;

(SEQ ID NO: 252)

Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-

NH 2 ;

(SEQ ID NO: 253)

Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-

NH 2 ;

or

(SEQ ID NO: 254)

Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-

NH 2 .

67 . The peptide or pharmaceutically acceptable salt thereof of claim 66 , wherein the peptide comprises two cysteine residues linked via a disulfide bond.

68 . A pharmaceutical composition comprising the peptide or pharmaceutically acceptable salt thereof of claim 57 and a pharmaceutically acceptable carrier or excipient.

69 . The pharmaceutical composition of claim 67 , wherein the peptide or pharmaceutically acceptable salt thereof comprises one of the following sequences:

(SEQ ID NO: 29)

DTHFPICIFGPRSKGWVC;

(SEQ ID NO: 38)

DTHFPCIIFGPRSKGWVCK;

(SEQ ID NO: 128)

DTHFPCIIFEPRSKGWVCK;

(SEQ ID NO: 164)

DTHFPCIIFGPRSKGWACK;

(SEQ ID NO: 168)

DTHFPCIIFGPRSKGWVCKK;

(SEQ ID NO: 57

DTHFPCIIFVCHRPKGCYRRVCR;

(SEQ ID NO: 125)

DTHFPCIKFGPRSKGWVCK;

(SEQ ID NO: 173)

DTHFPCIKFKPRSKGWVCK;

(SEQ ID NO: 106)

DTHFPCIIFGPRSRGWVCK;

(SEQ ID NO: 135)

DTHFPCIKFGPKSKGWVCK;

(SEQ ID NO: 207)

DTHFPCIKFEPRSKGCK;

(SEQ ID NO: 265)

DTHFPCIKFEPKSKGWECK;

(SEQ ID NO: 245)

DTHFPCIKFEPRSKKCK;

(SEQ ID NO: 247)

DTHFPCIKFEPRSKGCKK;

(SEQ ID NO: 249)

DTHFPCIKFKPRSKGCK;

or

(SEQ ID NO: 250)

DTHFPCIKFEPKSKGCK.

70 . The pharmaceutical composition of claim 68 , wherein the peptide or pharmaceutically acceptable salt thereof comprises one of the following structures:

(SEQ ID NO: 29)

Isovaleric acid-DTHFPICIFGPRSKGWVC-NH 2 ;

(SEQ ID NO: 38)

Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 128)

Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 ;

(SEQ ID NO: 164)

Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH 2 ;

(SEQ ID NO: 168)

Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH 2 ;

(SEQ ID NO: 57)

Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH 2 ;

(SEQ ID NO: 172)

Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 173)

Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 ;

(SEQ ID NO: 199)

Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVC-NH 2 ;

(SEQ ID NO: 200)

Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVC-NH 2 ;

(SEQ ID NO: 201)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 ;

(SEQ ID NO: 202)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH 2 ;

(SEQ ID NO: 203)

Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH 2 ;

(SEQ ID NO: 183)

Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 ;

(SEQ ID NO: 217)

Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH 2 ;

(SEQ ID NO: 219)

Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 ;

(SEQ ID NO: 220)

Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH 2 ;

(SEQ ID NO: 221)

Isovaleric acid-

DTHFPCIKFGPRSKGWVC(K(Palm))NH 2 ;

(SEQ ID NO: 222)

Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-

NH 2 ;

(SEQ ID NO: 223)

Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-

NH 2 ;

(SEQ ID NO: 224)

Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-

NH 2 ;

(SEQ ID NO: 225)

Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-

NH 2 ;

(SEQ ID NO: 226)

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-

NH 2 ;

(SEQ ID NO: 176)

Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-

NH 2 ;

(SEQ ID NO: 241)

Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-

NH 2 ;

(SEQ ID NO: 242)

Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-

NH 2 ;

(SEQ ID NO: 243)

Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-

NH 2 ;

(SEQ ID NO: 265)

Isovaleric acid-DTHFPCIKFEP(K(isoGlu-

Palm))SKGWECK-NH 2 ;

(SEQ ID NO: 244)

Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-

NH 2 ;

(SEQ ID NO: 245)

Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-

NH 2 ;

(SEQ ID NO: 246)

Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-

NH 2 ;

(SEQ ID NO: 248)

Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-

NH 2 ;

(SEQ ID NO: 249)

Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-

NH 2 ;

(SEQ ID NO: 250)

Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-

NH 2 ;

(SEQ ID NO: 251)

Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-

NH 2 ;

(SEQ ID NO: 252)

Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-

NH 2 ;

(SEQ ID NO: 253)

Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-

NH 2 ;

or

(SEQ ID NO: 254)

Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-

NH 2 .

71 . The pharmaceutical composition of claim 69 , wherein the peptide or pharmaceutically acceptable salt thereof comprises two cysteine residues linked via a disulfide bond.

72 . A method of treating a disease of iron metabolism in a subject, comprising administering to the subject at least one peptide or pharmaceutically acceptable salt thereof according to claim 57 or a pharmaceutical composition according to claim 67 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2017
From: SMYTHE, MARK LESLIE; BOURNE, GREGORY THOMAS; VINK, SIMONE; FREDERICK, BRIAN T.; MADALA, PRAVEEN
To: PROTAGONIST THERAPEUTICS, INC.
Reel/Frame 043838/0308 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2017
From: TOFTENG SHELTON, ANNE PERNILLE; FOG, JACOB ULRIK
To: ZEALAND PHARMA A/S
Reel/Frame 043838/0350 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2017
From: ZEALAND PHARMA/AS
To: PROTAGONIST THERAPEUTICS, INC.
Reel/Frame 043838/0366 →