Hepcidin analogues and uses thereof

1. A peptide having the following structural formula I′

(SEQ ID NO: 21)

R1′-X′-Y′-R2 (I′)

or a pharmaceutically acceptable salt or solvate 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′

(SEQ ID NO: 13)

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia′)

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′

(SEQ ID NO: 16)

Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15

(IIa′)

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 said peptide of formula I′ is optionally PEGylated on R1′, X′, or Y′, and wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety.

2. The peptide or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein R1′ is hydrogen, isovaleric acid, isobutyric acid or acetyl.

3. The peptide or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein X′ is a peptide sequence having formula Ib′

(SEQ ID NO: 14)

X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib′)

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.

4. The peptide or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein X′ is a peptide sequence having formula Ic′

(SEQ ID NO: 15)

X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic′)

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.

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

6. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein X′-Y′ of formula I′ 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;

(SEQ ID NO: 250)

DTHFPCIKFEPKSKGCK;

(SEQ ID NO: 314)

DTHFPCIKF;

(SEQ ID NO: 28)

DTHFPCIIF;

or

(SEQ ID NO: 325)

DTKFPCIIF,

wherein said peptide is optionally PEGylated on R1′, X′, or Y′, and wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety.

7. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6 , 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 ;

(SEQ ID NO: 254)

Isovaleric acid-

DTHFPCIKFEPRSKGC(K-(Dapa-Palm))-NH 2 ;

(SEQ ID NO: 314)

Isolvaleric acid-DTHFPCIKF-NH 2 ;

(SEQ ID NO: 314)

Hy-DTHFPCIKF-NH 2 ;

(SEQ ID NO: 28)

Isolvaleric acid-DTHFPCIIF-NH 2 ;

(SEQ ID NO: 28)

Hy-DTHFPCIIKF-NH 2 ;

(SEQ ID NO: 325)

Isovaleric acid-DTKFPCIIF-NH 2 ;

or

(SEQ ID NO: 325)

Hy-DTKFPCIIF-NH 2 .

8. A pharmaceutical composition comprising the peptide or pharmaceutically acceptable salt or solvate thereof of claim 6 and a pharmaceutically acceptable carrier or excipient.

9. A pharmaceutical composition comprising the peptide or pharmaceutically acceptable salt or solvate thereof of claim 7 and a pharmaceutically acceptable carrier or excipient.