Analogues of hepcidin mimetics with improved in vivo half lives

1. A hepcidin analogue comprising a polypeptide sequence or structure selected from the group consisting of:

Isovaleric acid-DTHFP-[Pen]-IKF-

[SEQ ID NO: 9]

[Lys(IsoGlu-Palm)]-PRSKG-[Pen]-K-NH 2

Isovaleric acid-DTHFP-[Pen]-IKF-

[SEQ ID NO: 10]

[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 11]

[Lys(IsoGlu-Palm)]-PRSKG-[Pen]-K-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 12]

[Lys(IsoGlu-Palm)]-PRSK-[Sar]-CK-NH 2

Isovaleric acid-DTH-[Dpa]-PCIKF-

[SEQ ID NO: 13]

[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTH-[Dpa]-PCIKF-

[SEQ ID NO: 14]

[Lys(IsoGlu-Palm)]-PRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 15]

[Lys(IsoGlu-Palm)]-PRSKGC-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 16]

[Lys(IsoGlu-Palm)]-PRSK-[Sar]-C-NH 2

Isovaleric acid-DTHFPCKKF-

[SEQ ID NO: 17]

[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 20]

[Lys(isoGlu-biotin)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 21]

[Lys(isoGlu-Isovaleric acid)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 22]

[Lys(PEG2-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 23]

[Lys(PEG11-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 24]

[Lys(PEG11-Lauric acid)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 25]

[Lys(PEG11-Myristic acid)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 28]

[Lys(Ahx-Palm)]-PRSKGCK-NH 2

Isovaleric acid-DTHFPCI-

[SEQ ID NO: 29]

[Lys(Ahx-Palm)]-FEPRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 30]

[Lys(Ahx-Palm)]-PRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCI-

[SEQ ID NO: 32]

[Lys(PEG11-Palm)]-FEPRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCIKF-

[SEQ ID NO: 33]

[Lys(PEG11-Palm)]-PRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCI-

[SEQ ID NO: 34]

[Lys(isoGlu-Ahx-Palm)]-FEPRSK-[Sar]-CK-NH 2

Isovaleric acid-DTHFPCI-

[SEQ ID NO: 35]

[Lys(OEG-OEG-isoGlu-(C18-diacid))]-

FEPRSK-[Sar]-CK-NH 2

[(Isovaleric acid-DTHFPCIRF) 2 ]-

[SEQ ID NO: 36]

Lys(IsoGlu-Octanoic acid)]-NH 2

(Isovaleric acid-DTHFPCIKF) 2 [Ida]-

[SEQ ID NO: 37], and

[βala]-(Peg2-Palm)

(Isovaleric acid-DTHFPCIKF) 2 [Ida]-

[SEQ ID NO: 38],

[βala](Peg11-Palm)]

or a pharmaceutically acceptable salt or solvate thereof.

2. A pharmaceutical composition comprising the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle.

3. A hepcidin analogue consisting of a polypeptide sequence or structure selected from the group consisting of:

Isovaleric acid-DTHFP-[Pen]-IKF-[Lys(IsoGlu-Palm)]-PRSKG-[Pen]-K-NH 2 [SEQ ID NO: 9]

Isovaleric acid-DTHFP-[Pen]-IKF-[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 10]

Isovaleric acid-DTHFPCIKF-[Lys(IsoGlu-Palm)]-PRSKG-[Pen]-K-NH 2 [SEQ ID NO: 11]

Isovaleric acid-DTHFPCIKF-[Lys(IsoGlu-Palm)]-PRSKG-[Sar]-CK-NH 2 [SEQ ID NO: 12]

Isovaleric acid-DTH-[Dpa]-PCIKF-[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 13]

Isovaleric acid-DTH-[DPpa]-PCIKF-[Lys(IsoGlu-Palm)]-PRSK-[Sar]-CK-NH 2 [SEQ ID NO: 14]

Isovaleric acid-DTHFPCIKF-[Lys(IsoGlu-Palm)]-PRSKGC-NH 2 [SEQ ID NO: 15]

Isovaleric acid-DTHFPCIKF-[Lys(IsoGlu-Palm)]-PRSK-[Sar]-C-NH 2 [SEQ ID NO: 16]

Isovaleric acid-DTHFPCKKF-[Lys(IsoGlu-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 17]

Isovaleric acid-DTHFPCIKF-[Lys(isoGlu-bioitin)]-PRSKGCK-NH 2 [SEQ ID NO: 20]

Isovaleric acid-DTHFPCIKF-[Lys(isoGlu-Isovaleric acid)]-PRSKGCK-NH 2 [SEQ ID NO: 21]

Isovaleric acid-DTHFPCIKF-[Lys(PEG2-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 22]

Isovaleric acid-DTHFPCIKF-[Lys(PEG11-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 23]

Isovaleric acid-DTHFPCIKF-[Lys(PEG11-Lauric acid)]-PRSKGCK-NH 2 [SEQ ID NO: 24]

Isovaleric acid-DTHFPCIKF-[Lys(PEG11-Myristic acid)]-PRSKGCK-NH 2 [SEQ ID NO: 25]

Isovaleric acid-DTHFPCIKF-[Lys(Ahx-Palm)]-PRSKGCK-NH 2 [SEQ ID NO: 28]

Isovaleric acid-DTHFPCI-[Lys(Ahx-Palm)]-FEPRSK-[Sar]-CK-NH 2 [SEQ ID NO: 29]

Isovaleric acid-DTHFPCIKF-[Lys(Ahx-Palm)]-PRSK-[Sar]-CK-NH 2 [SEQ ID NO: 30]

Isovaleric acid-DTHFPCI-[Lys(PEG11-Palm)]-FEPRSK-[Sar]-CK-NH 2 [SEQ ID NO: 32]

Isovaleric acid-DTHFPCIKF-[Lys(PEG11-Palm)]-PRSK-[Sar]-CK-NH 2 [SEQ ID NO: 33]

Isovaleric acid-DTHFPCI-[Lys(isoGlu-Ahx-Palm)]-FEPRSK-[Sar]-CK-NH 2 [SEQ ID NO: 34]

Isovaleric acid-DTHFPCI-[Lys(OEG-OEG-isoGlu-(C18-diacid))]-FEPRSK-

[Sar]-CK-NH 2 [SEQ ID NO: 35]

[(Isovaleric acid-DTHFPCIRF) 2 -[Lys(IsoGlu-Octanoic acid)]-NH 2 [SEQ ID NO: 36]

Isovaleric acid-DTHFPCIKF) 2 -Ida-[βala]-(Peg2-Palm), [SEQ ID NO: 37] and

Isovaleric acid-DTHFPCIKF) 2 -Ida-[βala]-(Peg11-Palm)] [SEQ ID NO: 38].

or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition comprising the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 3 , and a pharmaceutically acceptable carrier, excipient or vehicle.

5. A method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with at least one hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of claim 1 .

6. A method for treating a disease of iron metabolism in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition of claim 2 , wherein the disease of iron metabolism is selected from the group consisting of hereditary hemochromatosis, iron hemochromatosis, human factors engineering (HFE) mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, and thalassemia.

7. The method of claim 6 , wherein the disease of iron metabolism is thalassemia, wherein thalassemia is selected from the group consisting of thalassemia intermedia , alpha thalassemia and β-thalassemia.

8. The method of claim 6 , wherein the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, vaginal, or topical route of administration.

9. The method of claim 8 , wherein the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration.

10. The method of claim 6 , wherein the pharmaceutical composition is provided to the subject at most twice daily, at most once daily, at most once every two days, at most once a week, or at most once a month.

11. The method of claim 6 , wherein the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof is provided to the subject at a dosage of about 1 mg to about 100 mg.