Hepcidin analogues and uses thereof

1. A peptide having the following structural formula I′

R 1 ′-X′-Y′-R 2 ′  (I′) (SEQ ID NO:21)

or a pharmaceutically acceptable salt or solvate thereof,

wherein

R 1 ′ is hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aryl, C 6 -C 12 aryl C 1 -C 6 alkyl, C 1 -C 20 alkanoyl or pGlu;

R 2 ′ 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, 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, Ala, D-His or Lys;

X4 is Phe, Ala, Dpa, bhPhe or D-Phe;

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;

Y′ is a peptide 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 at least one of Y1, Y2, Y8, Y9, Y11, Y13, or Y14 is Cys;

wherein said compound of formula I′ is optionally PEGylated on X′, or Y′; and

wherein when said compound of formula I′ comprises two or more cysteine residues, at least two of said cysteine residues being linked via a disulfide bond.

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

3. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein X′ is a peptide having formula Ia′ and wherein

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

X2 is Thr, Ala, or D-Thr;

X3 is His, 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.

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

5. The peptide of formula or I′ pharmaceutically acceptable salt or solvate thereof according to claim h, wherein X′ is a peptide 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.

6. The peptide of forumla I′ pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Y′ is a peptide having formula IIb′

Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10  (IIb′) (SEQ ID NO:17)

wherein

Y1 is Gly, Ala, Lys, Pro or D-Pro;

Y2 is Pro, Ala or Gly;

Y3 is Arg, Ala, Lys or Trp;

Y4 is Ser, Gly or Ala;

Y5 is Lys, Met, Arg or Ala;

Y6 is Gly, Arg or Ala;

Y7 is Trp or Ala;

Y8 is Val, Thr, Ala or Glu; and

Y10 is Met, Lys or absent.

7. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Y′ is a peptide having formula IIc′

Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10  (IIc′) (SEQ ID NO:18)

wherein

Y1 is Gly, Pro or D-Pro;

Y2 is Pro or Gly;

Y3 is Arg or Lys;

Y8 is Val or Thr; and

Y10 is Met, Lys or absent.

8. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Y′ is a peptide having the formula IId′

Y1-Cys-Y3-Y4-Arg-Y6-Y7-Y8-Cys-Y10-Y11-Y12-Y13-Y14-Y15  (IId′) (SEQ ID NO:19)

wherein

Y1 is Val or Ala or absent;

Y3 is Gly, Pro or absent;

Y4 is His, Trp or Tyr;

Y6 is Ser, Gly or Pro;

Y7 is Ile, Gly or Lys;

Y8 is Gly, Met or absent;

Y10 is Tyr or Cys;

Y11 is Arg, Lys, Met or Ala;

Y12 is Arg or Ala;

Y13 is Cys or Val or absent;

Y14 is Cys, Lys, Pro, Arg, Thr or absent; and

Y15 is Arg, Thr or absent.

9. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein Y′ is a peptide having the formula IIe′

Val-Cys-Y3-His-Arg-Y6-Y7-Y8-Cys-Tyr-Arg-Y12-Y13-Y14-Y15  (IIe′) (SEQ ID NO:20)

wherein

Y3 is Gly or absent;

Y6 is Ser or Pro;

Y7 is Ile or Lys;

Y8 is Gly or absent;

Y12 is Arg or Ala;

Y13 is Cys or Val or absent;

Y14 is Cys, Arg, Thr or absent; and

Y15 is Arg or absent.

10. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein the peptide exhibits hepcidin activity.

11. The peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein the peptide binds ferroportin.

12. A composition which comprises at least one peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 .

13. A method of treating a disease of iron metabolism in a subject which comprises administering at least one peptide of formula I′ or pharmaceutically acceptable salt or solvate thereof according to claim 1 or the composition according to claim 12 to the subject; wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (High Iron Fe) mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepicidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia.

14. The method of claim 13 , wherein the disease of iron metabolism is the transfusional iron overload disease.

15. The method of claim 13 , wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (High Iron Fe) mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, or neonatal hemochromatosis.

16. The method of claim 13 , wherein the disease of iron metabolism is the thalassemia.

17. The method of claim 16 , wherein the thalassemia is thalassemia intermedia, alpha thalassemia, or β-thalassemia.

18. The method of claim 17 , wherein the disease of iron metabolism is β-thalassemia.

19. The method of claim 15 , wherein the disease of iron metabolism is hereditary hemochromatosis (HH).