BHANDARI ASHOK (US)
ZHANG JIE (US)
FREDERICK BRIAN TROY (US)
SMYTHE MARK LESLIE (AU)
WO1998033524A1 | 1998-08-06 |
PATERSON IAN C, CHARNLEY A KEITH, COOPER RICHARD M, CLARKSON JOHN M: "Partial characterization of specific inducers of a cuticle-degrading protease from the insect pathogenic fungus Metarhiziurn anisopliae", MICROBIOLOGY, 1 January 1994 (1994-01-01), pages 3153 - 3159, XP055906023, Retrieved from the Internet
GOPTAR I. A., KOULEMZINA I. A., FILIPPOVA I. YU., LYSOGORSKAYA E. N., OKSENOIT E. S., ZHUZHIKOV D. P., DUNAEVSKY YA. E., BELOZERSK: "Properties of post-proline cleaving enzymes from Tenebrio molitor", RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, PLEIADES PUBLISHING, MOSCOW, vol. 34, no. 3, 1 May 2008 (2008-05-01), Moscow, pages 280 - 285, XP055906025, ISSN: 1068-1620, DOI: 10.1134/S1068162008030047
CLAIMS What is claimed is: 1. A hepcidin analogue comprising a peptide according to Formula Ia: R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-R2 (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-C6 alkyl, C1-C20 alkanoyl, or C1-C20 cycloalkanoyl; R2 is NH2, substituted amino, OH, or substituted hydroxy; X1 is absent, or is Asp, isoAsp, Asp(OMe), Glu, Glu-OMe, bhGlu, bGlu, substituted Glu, Gly, N-substituted Gly, Gla, Glp, Ala, Arg, Dab, Leu, Lys, Dap, Orn, (D)Asp, (D)Arg, Tet1, or Tet2, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X2 is Ala, Thr, Gly, N-substituted Gly, or Ser; X3 is Ala, Gly, N-substituted Gly, His, or substituted His; X4 is Ala, Phe, Dpa, Gly, N-substituted Gly, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; X5 is Pro, D-Pro, bhPro, D-bhPro, NPC, D-NPC, Gaba, 2-Pyrrolidinepropanoic acid (Ppa), 2- Pyrrolidinebutanoic acid (Pba), Glu, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X6 is absent or is any amino acid other than Cys, (D)Cys, aMeCys, hCys, or Pen; X7 is absent, or is Ala, Gly, N-substituted Gly, Ile, Val, Leu, NLeu, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X8 is absent or is Ala, (D)Ala, Ile, Gly, N-substituted Gly, Glu, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, substituted (D)Lys, aMeLys, or 123Triazole ; X9 is absent, or is Ala, Ile, Gly, N-substituted Gly, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X10 is absent, or is Ala, Gly, N-substituted Gly, Ile, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X11 is absent, or is Ala, Pro, bhPhe, Lys, substituted Lys, or (D)Lys; and each of X12-X14 is absent, or is independently any amino acid; provided that: i) the peptide may further be conjugated at any amino acid; ii) any of the amino acids of the peptide may be the corresponding (D)-amino acid of the amino acid or may be N-substituted; and iii) the peptide is a linear peptide or is a cyclized lactam; and wherein Dapa is diaminopropanoic acid; Dpa or DIP is 3,3-diphenylalanine or b,b- diphenylalanine; bhPhe is b-homophenylalanine; Bip is biphenylalanine; bhPro is b- homoproline; Tic is L-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid; NPC is L-nipecotic acid; bhTrp is b-homoTryptophane; 1-Nal is 1-naphthylalanine; 2-Nal is 2-naphthylalanine; Orn is orinithine; Nleu is norleucine; 2Pal is 2-pyridylalanine; Ppa is 2-(R)- Pyrrolidinepropanoic acid, Pba is 2-(R)-Pyrrolidinebutanoic acid; substituted Phe is phenylalanine wherein phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azido, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; substituted bhPhe is b-homophenylalanine wherein phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azido, nitro, 4- carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; substituted Trp is N-methyl-L-tryptophan, a-methyltryptophan, or tryptophan substituted with F, Cl, OH, or t-Bu; substituted bhTrp is N-methyl-L-b-homotryptophan, a-methyl-b-homotryptophan, or b- homotryptophan substituted with F, Cl, OH, or t-Bu; Tet1 is (S)-(2-amino)-3-(2H-tetrazol-5-yl)propanoic acid; and Tet2 is (S)-(2-amino)-4-(1H- tetr l 5 l b t i id 12 Dab is . 2. A hepcidin analogue comprising a peptide according to Formula Ib: R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-R2 (Ib) or a pharmaceutically acceptable salt or solvate thereof wherein: R1 is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-C6 alkyl, C1-C20 alkanoyl, or C1-C20 cycloalkanoyl; R2 is NH2, substituted amino, OH, or substituted hydroxy; X1 is absent, or is Asp, isoAsp, Asp(OMe), Glu, Glu-OMe, bhGlu, bGlu, Gly, N-substituted Gly, Gla, Glp, Ala, Arg, Leu, Lys, Dap, Orn, (D)Asp, (D)Arg, Tet1, or Tet2; X2 is Ala, Thr, Gly, N-substituted Gly, or Ser; X3 is Ala, Gly, N-substituted Gly, His, or substituted His; X4 is Phe, Dpa, Gly, N-substituted Gly, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; X5 is Pro, D-Pro, bhPro, D-bhPro, NPC, D-NPC, Gaba, 2-Pyrrolidinepropanoic acid (Ppa), or 2-Pyrrolidinebutanoic acid (Pba); X6 is absent or is any amino acid other than Cys, (D)Cys, aMeCys, hCys, or Pen; X7 is absent, or is Ala, Gly, N-substituted Gly, Ile, Val, Leu, NLeu, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X8 is absent or is Ala, (D)Ala, Ile, Gly, N-substituted Gly, Glu, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, substituted (D)Lys, or aMeLys; X9 is absent, or is Ala, Ile, Gly, N-substituted Gly, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X10 is absent, or is Ala, Gly, N-substituted Gly, Ile, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X11 is absent, or is Ala, Pro, bhPhe, Lys, substituted Lys, or (D)Lys; and each of X12-X14 is absent, or is independently any amino acid; provided that: i) the peptide may further be conjugated at any amino acid; ii) any of the amino acids of the peptide may be the corresponding (D)-amino acid of the amino acid or may be N-substituted; and wherein Dapa is diaminopropanoic acid; Dpa or DIP is 3,3-diphenylalanine or b,b- diphenylalanine; bhPhe is b-homophenylalanine; Bip is biphenylalanine; bhPro is b- homoproline; Tic is L-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid; NPC is L-nipecotic acid; bhTrp is b-homoTryptophane; 1-Nal is 1-naphthylalanine; 2-Nal is 2-naphthylalanine; Orn is orinithine; Nleu is norleucine; 2Pal is 2-pyridylalanine; Ppa is 2-(R)- Pyrrolidinepropanoic acid Pba is 2-(R)-Pyrrolidinebutanoic acid; substituted Phe is phenylalanine wherein phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azido, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; substituted bhPhe is b-homophenylalanine wherein phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azido, nitro, 4- carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; substituted Trp is N-methyl-L-tryptophan, a-methyltryptophan, or tryptophan substituted with F, Cl, OH, or t-Bu; substituted bhTrp is N-methyl-L-b-homotryptophan, a-methyl-b-homotryptophan, or b- homotryptophan substituted with F, Cl, OH, or t-Bu; Tet1 is (S)-(2-amino)-3-(2H-tetrazol-5-yl)propanoic acid; and Tet2 is (S)-(2-amino)-4-(1H- tetrazol-5-yl)butanoic acid. 3. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X1 is Asp, Glu, (D)Asp, Tet1 or Tet2; X2 is Thr or Ser; X3 is His or substituted His, X7 is absent, or is Ile, Val, Leu, NLeu, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X8 is absent, or is Ile, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, substituted (D)Lys, or aMeLys; X9 is absent, or is Ala, Ile, Gly, N-substituted Gly, Val, Leu, NLeu, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X10 is absent, or is Ala, Ile, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; and X11 is absent, or is Pro, bhPhe, Lys, substituted Lys, or (D)Lys. 4. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X1 is Glu, Dab, Dap, Orn, Lys, or Tet1; X2 is Thr; X3 is His or 1MeHis; X4 is Dpa; X5 is Pro; X6 is absent, Ala, Glu, or substituted Lys; X7 is absent, or is Ile, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; X8 is absent, or is Ile, Glu, Asp, 123Triazole, Lys, substituted Lys, (D)Lys, substituted (D)Lys, or aMeLys; X9 is absent, or is bhPhe; X10 is absent, or is Ala, Ile, Phe, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys; and X11 is absent, or is Pro, bhPhe, Lys, substituted Lys, or (D)Lys. 5. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-4, wherein X1 is Glu. 6. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-4, wherein X2 is Thr. 7. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-4, wherein X4 is Dpa. 8. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-4, wherein X5 is Pro. 9. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-8, wherein the peptide is according to Formula II: R1-Glu-Thr-X3-[Dpa]-Pro-X6-X7-X8-X9-X10-X11-X12-X13-X14-R2 (II) wherein R1, R2, X3, X6-X14 are as in claim 1 or claim 2. 10. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-9, wherein X9 is absent, bhPhe, Lys, substituted Lys, (D)Lys, or substituted (D)Lys. 11. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-9, wherein X9 is absent. 12. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-9, wherein X9 is bhPhe. 13. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-12, wherein the peptide is according to Formula III: R1-Glu-Thr-X3-[Dpa]-Pro-X6-X7-X8-[bhPhe]-X10-X11-X12-X13-X14-R2 (III) wherein R1, R2, X3, X6-X8, and X10-X14 are as in claim 1 or claim 2. 14. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-13, wherein X6 is Ala, Lys, or substituted Lys. 15. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-13, wherein X6 is Ala. 16. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-15, wherein the peptide is according to Formula IV: R1-Glu-Thr-X3-[Dpa]-Pro-Ala-X7-X8-[bhPhe]-X10-X11-X12-X13-X14-R2 (IV) wherein R1, R2, X3, X7-X8, and X10-X14 are as in claim 1 or claim 2. 17. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-16, wherein X7 is absent, Ile, Lys, or substituted Lys. 18. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-16, wherein X7 is absent. 19. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-16, wherein X7 is Ile. 20. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-18, wherein the peptide is according to Formula V: R1-Glu-Thr-X3-[Dpa]-Pro-Ala-Ile-X8-[bhPhe]-X10-X11-X12-X13-X14-R2 (V) wherein R1, R2, X3, X8, and X10-X14 are as in claim 1 or claim 2. 21. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-20, wherein X8 is Lys, substituted Lys, (D)Lys, or substituted (D)Lys. 22. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-20, wherein X8 is (D)Lys, or substituted (D)Lys. 23. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-20, wherein X8 is Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). 24. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-23, wherein the peptide is according to Formula VIa, VIb, or VIc: R1-Glu-Thr-X3-[Dpa]-Pro-Ala-Ile-[(D)Lys]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIa); R1-Glu-Thr-X3-[Dpa]-Pro-Ala-Ile-[Lys(Ac)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIb); or R1-Glu-Thr-X3-[Dpa]-Pro-Ala-Ile-[Lys]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIc); wherein R1, R2, X3, and X10-X14 are as in claim 1 or claim 2. 25. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-24, wherein X8 is a conjugated amino acid. 26. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-24, wherein X8 is conjugated Lys or (D)Lys. 27. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-24, wherein X8 is Lys(L1Z) or (D)Lys(L1Z), 28. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-24, wherein X3 is His. 29. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula VIIa, VIIb, or VIIc: R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[(D)Lys]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIIa); R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(Ac)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIIb), or R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIIc); wherein R1, R2, and X10-X14 are as in claim 1 or claim 2. 30. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-29, wherein X3 is (1-Me)His. 31. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof e according to any one of claims 1-30, wherein the peptide is according to Formula VIIIa or VIIIb: R1-Glu-Thr-[(1-Me)His]-[Dpa]-Pro-Ala-Ile-[(D)Lys]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIIIa); or R1-Glu-Thr-[(1-Me)His]-[Dpa]-Pro-Ala-Ile-[Lys(Ac)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (VIIIb) wherein R1, R2, and X10-X14 are as in claim 1 or claim 2. 32. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-31, wherein X10 is Lys, substituted Lys, (D)Lys, or substituted (D)Lys. 33. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-31, wherein X10 is (D)Lys, or substituted (D)Lys 34. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-31, wherein X10 is (D)Lys, or (D)Lys(Ac). 35. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-31, wherein X10 is Lys(Ahx_Palm). 36. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-35, wherein X10 is a conjugated amino acid. 37. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-35, wherein X10 is conjugated Lys or (D)Lys. 38. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-35, wherein X10 is Lys(L1Z) or (D)Lys(L1Z), wherein L1 is a linker, and wherein Z is a half-life extension moiety. 39. The hepcidin analogue according to either of claims 30 or 38, wherein L1 is a single bond. 40. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to either of claims 30 or 36, wherein L1 is iso-Glu. 41. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein L1 is Ahx. 42. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein L1 is iso-Glu-Ahx. 43. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein L1 is PEG. 44. The hepcidin analogueor pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein L1 is PEG-Ahx. 45. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein L1 is iso-Glu-PEG-Ahx. 46. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 41, wherein PEG is –[C(O)-CH2-(Peg)n-N(H)]m-, or –[C(O)- CH2-CH2-(Peg)n-N(H)]m-; and Peg is -OCH2CH2-, m is 1, 2, or 3; and n is an integer between 1-100, or is 10K, 20K, or 30K. 47. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein m is 1. 48. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein m is 2. 49. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 2. 50. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 4. 51. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 8. 52. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 11. 53. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 12. 54. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein n is 20K. 55. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 1Peg2; and 1Peg2 is -C(O)- CH2-(Peg)2-N(H)-. 56. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 2Peg2; and 2Peg2 is -C(O)- CH2-CH2-(Peg)2-N(H)-. 57. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 1Peg2-1Peg2; and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-. 58. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 1Peg2-1Peg2; and 1Peg2- 1Peg2 is –[(C(O)-CH2–(OCH2CH2)2-NH-C(O)-CH2–(OCH2CH2)2-NH-]-. 59. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 2Peg4; and 2Peg4 is -C(O)- CH2-CH2-(Peg)4-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)4-NH]-. 60. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 1Peg8; and 1Peg8 is -C(O)- CH2-(Peg)8-N(H)-, or –[C(O)-CH2–(OCH2CH2)8-NH]-. 61. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 2Peg8; and 2Peg8 is -C(O)- CH2-CH2-(Peg)8-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)8-NH]-. 62. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 1Peg11; and 1Peg11 is - C(O)-CH2-(Peg)11-N(H)-, or –[C(O)-CH2–(OCH2CH2)11-NH]-. 63. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 2Peg11; and 2Peg11 is - C(O)-CH2-CH2-(Peg)11-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)11-NH]-. 64. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein PEG is 2Peg11’ or 2Peg12; and 2Peg11’ or 2Peg12 is -C(O)-CH2-CH2-(Peg)12-N(H)-, or –[C(O)-CH2-CH2– (OCH2CH2)12-NH]-. 65. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein when PEG is attached to Lys, the - C(O)- of PEG is attached to Ne of Lys. 66. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein when PEG is attached to isoGlu, the -N(H)- of PEG is attached to -C(O)- of isoGlu. 67. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein when PEG is attached to Ahx, the - N(H)- of PEG is attached to -C(O)- of Ahx. 68. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38, wherein when PEG is attached to Palm, the - N(H)- of PEG is attached to -C(O)- of Palm. 69. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-38 wherein Z is Palm 70. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula IXa or IXb: R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-X11-X12-X13-X14- R2 (IXa); or R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(Ac)]-[bhPhe]-[Lys(Ahx_Palm)]-X11-X12-X13- X14-R2 (IXb) wherein R1, R2, and X11-X14 are as in claim 1 or claim 2. 71. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptideis according to Formula Xa or Xb: R1-Glu-Thr-[(1-Me)His]-[Dpa]-Pro-Ala-Ile-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-X11-X12- X13-X14-R2 (Xa); or R1-Glu-Thr-[(1-Me)His]-[Dpa]-Pro-Ala-Ile-[Lys(Ac)]-[bhPhe]-[Lys(Ahx_Palm)]-X11-X12- X13-X14-R2 (Xb) wherein R1, R2, and X11-X14 are as in claim 1 or claim 2. 72. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-71, wherein the peptide is a linear peptide. 73. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-71, wherein the peptide is a lactam. 74. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-71, wherein the peptide is a lactam, wherein any free -NH2 is cyclized with any free -C(O)2H. 75. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXI: R1-Glu-Thr-His-[Dpa]-Pro-X6-X7-X8-X9-X10-X11-X12-X13-X14-R2 (XXI), h i R1 R2 d X10 X14 i l i 1 l i 2 X6 is absent, Ala, or substituted Lys; X7 is absent, Ile, substituted Lys, or substituted (D)Lys; X9 is absent or bhPhe; and X8 is Lys(L1Z) or (D)Lys(L1Z), wherein L1 is a linker and Z is a half-life extension moiety. 76. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 75, wherein X8 is Lys(L1Z). 77. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 75, wherein X8 is (D)Lys(L1Z). 78. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXII: R1-Glu-Thr-His-[Dpa]-Pro-X6-X7-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXII), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2; X6 is absent, Ala, or substituted Lys; X7 is absent, Ile, substituted Lys, or substituted (D)Lys; X9 is absent or bhPhe. 79. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 75-78, wherein X6 is absent. 80. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 75-78, wherein X6 is substituted Lys. 81. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 75-78, wherein X6 is Ala. 82. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXIIIa or XXIIIb: R1-Glu-Thr-His-[Dpa]-Pro-X7-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIIIa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-X7-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIIIb), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2; X7 is absent, Ile, substituted Lys, or substituted (D)Lys; X9 is absent or bhPhe. 83. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-82 wherein X7 is absent 84. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-82, wherein X7 is substituted (D)Lys. 85. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-82, wherein X7 is substituted Lys. 86. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-82, wherein X7 is Ile. 87. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXIVa, XXIVb, XXIVc, or XXIVd: R1-Glu-Thr-His-[Dpa]-Pro-Ile-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIVa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIVb), R1-Glu-Thr-His-[Dpa]-Pro- [Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIVc), R1-Glu-Thr-His-[Dpa]-Pro-Ala-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXIVd), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2; X9 is absent or bhPhe. 88. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-87, wherein X9 is absent. 89. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXVa, XXVb, XXVc, or XXVd: R1-Glu-Thr-His-[Dpa]-Pro-Ile-[Lys(L1Z)]-X10-X11-X12-X13-X14-R2 (XXVa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(L1Z)]-X10-X11-X12-X13-X14-R2 (XXVb), R1-Glu-Thr-His-[Dpa]-Pro- [Lys(L1Z)]-X10-X11-X12-X13-X14-R2 (XXVc), R1-Glu-Thr-His-[Dpa]-Pro-Ala-[Lys(L1Z)]-X10-X11-X12-X13-X14-R2 (XXVd), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2. 90. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-87, wherein X9 is bhPhe. 91. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXVIa, XXVIb, XXVIc, or XXVId: R1-Glu-Thr-His-[Dpa]-Pro-Ile-[Lys(L1Z)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (XXVIa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(L1Z)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (XXVIb), R1-Glu-Thr-His-[Dpa]-Pro- [Lys(L1Z)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (XXVIc), R1-Glu-Thr-His-[Dpa]-Pro-Ala-[Lys(L1Z)]-[bhPhe]-X10-X11-X12-X13-X14-R2 (XXVId), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2. 92. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-91, wherein X10 is Lys or (D)Lys. 93. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-91, wherein X10 is (D)Lys. 94. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXVIIa, XXVIIb, XXVIIc, or XXVIId: R1-Glu-Thr-His-[Dpa]-Pro-Ile-[Lys(L1Z)]-[bhPhe]-[(D)Lys]-X11-X12-X13-X14-R2 (XXVIIa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(L1Z)]-[bhPhe]-[(D)LYS]-X11-X12-X13-X14-R2 (XXVIIb), R1-Glu-Thr-His-[Dpa]-Pro- [Lys(L1Z)]-[bhPhe]-[(D)LYS]-X11-X12-X13-X14-R2 (XXVIIc), R1-Glu-Thr-His-[Dpa]-Pro-Ala-[Lys(L1Z)]-[bhPhe]-[(D)LYS]-X11-X12-X13-X14-R2 (XXVIId), wherein R1, R2, and X11-X14 are as in claim 1 or claim 2. 95. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-91, wherein X10 is absent. 96. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the peptide is according to Formula XXVIIIa, XXVIIIb XXVIIIc or XXVIIId: R1-Glu-Thr-His-[Dpa]-Pro-Ile-[Lys(L1Z)]-[bhPhe]-X11-X12-X13-X14-R2 (XXVIIIa), R1-Glu-Thr-His-[Dpa]-Pro-Ala-Ile-[Lys(L1Z)]-[bhPhe]-X11-X12-X13-X14-R2 (XXVIIIb), Phe]-X11-X12-X13-X14-R2 (XXVIIIc), R -Glu-Thr-His-[Dpa]-Pro-Ala-[Lys(L1Z)]-[bhPhe]-X11-X12-X13-X14-R2 (XXVIIId), wherein R1, R2, and X11-X14 are as in claim 1 or claim 2. 97. The hepcidin analogue according to any one of claims 78-96, wherein L1 is a single bond. 98. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is iso-Glu. 99. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is Ahx. 100. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is iso-Glu-Ahx. 101. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is PEG. 102. The hepcidin analogueor pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is PEG-Ahx. 103. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1 is iso-Glu-PEG-Ahx. 104. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to claim 41, wherein PEG is –[C(O)-CH2-(Peg)n-N(H)]m-, or –[C(O)- CH2-CH2-(Peg)n-N(H)]m-; and Peg is -OCH2CH2-, m is 1, 2, or 3; and n is an integer between 1-100, or is 10K, 20K, or 30K. 105. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96 wherein m is 1 106. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein m is 2. 107. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 2. 108. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 4. 109. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 8. 110. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 11. 111. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 12. 112. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein n is 20K. 113. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 1Peg2; and 1Peg2 is -C(O)- CH2-(Peg)2-N(H)-. 114. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 2Peg2; and 2Peg2 is -C(O)- CH2-CH2-(Peg)2-N(H)-. 115. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 1Peg2-1Peg2; and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-. 116. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 1Peg2-1Peg2; and 1Peg2- 1Peg2 is –[(C(O)-CH2–(OCH2CH2)2-NH-C(O)-CH2–(OCH2CH2)2-NH-]-. 117. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 2Peg4; and 2Peg4 is -C(O)- CH2-CH2-(Peg)4-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)4-NH]-. 118. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 1Peg8; and 1Peg8 is -C(O)- CH2-(Peg)8-N(H)-, or –[C(O)-CH2–(OCH2CH2)8-NH]-. 119. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 2Peg8; and 2Peg8 is -C(O)- CH2-CH2-(Peg)8-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)8-NH]-. 120. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 1Peg11; and 1Peg11 is - C(O)-CH2-(Peg)11-N(H)-, or –[C(O)-CH2–(OCH2CH2)11-NH]-. 121. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 2Peg11; and 2Peg11 is - C(O)-CH2-CH2-(Peg)11-N(H)-, or –[C(O)-CH2-CH2–(OCH2CH2)11-NH]-. 122. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein PEG is 2Peg11’ or 2Peg12; and 2Peg11’ or 2Peg12 is -C(O)-CH2-CH2-(Peg)12-N(H)-, or –[C(O)-CH2-CH2– (OCH2CH2)12-NH]-. 123. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein when PEG is attached to Lys, the - C(O)- of PEG is attached to Ne of Lys. 124. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein when PEG is attached to isoGlu, the -N(H)- of PEG is attached to -C(O)- of isoGlu. 125. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein when PEG is attached to Ahx, the - N(H)- of PEG is attached to -C(O)- of Ahx. 126. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein when PEG is attached to Palm, the -N(H)- of PEG is attached to -C(O)- of Palm. 127. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein Z is Palm. 128. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1Z is -Ahx_Palm. 129. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1Z is -bAla_Palm. 130. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96 wherein L1Z is -IsoGlu Palm 131. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1Z is PEG12_Palm. 132. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein L1Z is – 1PEG2_1PEG2_Ahx_C18_diacid. 133. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-96, wherein each of X11, X12, X13, and X14 is absent. 134. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 78-78, wherein the peptide is according to Formula XXI: R1-Glu-Thr-His-[Dpa]-Pro-X6-X7-[Lys(L1Z)]-X9-X10-X11-X12-X13-X14-R2 (XXI), wherein R1, R2, and X10-X14 are as in claim 1 or claim 2; X6 is absent, or substituted Lys; X7 is absent, or substituted Lys; X9 is absent or bhPhe. 135. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein each of -L1Z is indendently: PEG11_OMe; PEG12_ C18 acid; 1PEG2_1PEG2_Ahx_Palm; 1PEG2_Ahx_Palm; Ado_Palm; Ahx_Palm; Ahx_PEG20K; PEG12_Ahx_IsoGlu_Behenic; PEG12_Ahx_Palm; PEG12_DEKHKS_Palm; PEG12_IsoGlu_C18 acid; PEG12_Ahx_C18 acid; PEG12_IsoGlu_Palm; PEG12_KKK_Palm; PEG12 KKKG Palm; PEG12_DEKHKS_Palm; PEG12_Palm; PEG12_PEG12_Palm; PEG20K; PEG4_Ahx_Palm; PEG4_Palm; PEG8_Ahx_Palm; or IsoGlu_Palm; -1PEG2_1PEG2_Dap_C18_Diacid; -1PEG2_1PEG2_IsoGlu_C10_Diacid; -1PEG2_1PEG2_IsoGlu_C12_Diacid; -1PEG2_1PEG2_IsoGlu_C14_Diacid; -1PEG2_1PEG2_IsoGlu_C16_Diacid; -1PEG2_1PEG2_IsoGlu_C18_Diacid; -1PEG2_1PEG2_IsoGlu_C22_Diacid; -1PEG2_1PEG2_Ahx_C18_Diacid; -1PEG2_1PEG2_ C18_Diacid; -1PEG8_IsoGlu_C18_Diacid; -IsoGlu_C18_Diacid; -PEG12_Ahx_C18_Diacid; -PEG12_C16_Diacid; -PEG12_C18_Diacid; -1PEG2_1PEG2_1PEG2_ C18_Diacid; -1PEG2_1PEG2_1PEG2_ IsoGlu_C18_Diacid; -PEG12_IsoGlu_C18_Diacid; -PEG4_IsoGlu_C18_Diacid; or -PEG4_PEG4_IsoGlu_C18_Diacid; wherein PEG11_OMe is –[C(O)-CH2-CH2–(OCH2CH2)11-OMe]; 1PEG2 is –C(O)-CH2–(OCH2CH2)2-NH-; PEG4 is –C(O)-CH2-CH2–(OCH2CH2)4-NH-; PEG8 is –[C(O)-CH2-CH2–(OCH2CH2)8-NH-; 1PEG8 is –[C(O)-CH2–(OCH2CH2)8-NH-; PEG12 is –[C(O)-CH2-CH2–(OCH2CH2)12-NH-; Cn acid is -C(O)(CH2)n-2-CH3; C18 acid is -C(O)-(CH2)16-Me; Palm is -C(O)-(CH2)14-Me; isoGlu is isoglutamic acid; is ; A hx is –[C(O)-(CH2)5-NH]-; Cn_Diacid is -C(O)-(CH2)n-2-COOH; wherein n is 10, 12, 14, 16, 18, or 22. 136. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(1PEG2_1PEG2_IsoGlu_Cn_Diacid); and Lys(1PEG2_1PEG2_IsoGlu_Cn_Diacid) is and n is 10, 12, 14, 16, or 18. 137. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(1PEG2_1PEG2_IsoGlu_Cn_Diacid); and (D)Lys(1PEG2_1PEG2_IsoGlu_Cn_Diacid) is and n is 10, 12, 14, 16, or 18. 138. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(1PEG8_IsoGlu_Cn_Diacid); and Lys(1PEG8_IsoGlu_Cn_Diacid) is an d n is 10, 12, 14, 16, or 18. 139. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(1PEG8_IsoGlu_Cn_Diacid); and (D)Lys(1PEG8_IsoGlu_Cn_Diacid) is and n is 10, 12, 14, 16, or 18. 140. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(1PEG2_1PEG2_Dap_Cn_Diacid); and Lys(1PEG2_1PEG2_Dap_Cn_Diacid) is and n is 10, 12, 14, 16, or 18. 141. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(IsoGlu_Cn_Diacid); and Lys(IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 142. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(IsoGlu_Cn_Diacid); and (D)Lys(IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 143. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG12_IsoGlu_Cn_Diacid); and Lys(PEG12_IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 144. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(PEG12_IsoGlu_Cn_Diacid); and (D)Lys(PEG12_IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 145. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG4_IsoGlu_Cn_Diacid); and Lys(PEG4_IsoGlu_Cn_Diacid) is ; and n is 10 12 14 16 or 18 146. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(PEG4_IsoGlu_Cn_Diacid); and (D)Lys(PEG4_IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 147. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG4_PEG4_IsoGlu_Cn_Diacid); and Lys(PEG4_PEG4_IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 148. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(PEG4_PEG4_IsoGlu_Cn_Diacid); and (D)Lys(PEG4_PEG4_IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 149. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(IsoGlu_Cn_Diacid); and Lys(IsoGlu_Cn_Diacid) is ; an d n is 10, 12, 14, 16, or 18. 150. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(IsoGlu_Cn_Diacid); and (D)Lys(IsoGlu_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18 151. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG12_Ahx_Cn_Diacid); and Lys(PEG12_Ahx_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 152. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG12_Ahx_Cn_Diacid); and Lys(PEG12_Ahx_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 153. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(PEG12_Ahx_Cn_Diacid); and (D)Lys(PEG12_Ahx_Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 154. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is Lys(PEG12_ Cn_Diacid); and Lys(PEG12_ Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 155. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is (D)Lys(PEG12_ Cn_Diacid); and (D)Lys(PEG12_ Cn_Diacid) is ; and n is 10, 12, 14, 16, or 18. 156. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-134, wherein X8 or X10 is 123Triazole. 157. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-156, wherein X11 is absent, Ala, (D)Lys, or substituted Lys. 158. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-156, wherein X11 is absent. 159. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof 160. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-156, wherein X11 is (D)Lys. 161. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-156, wherein X11 is Lys(Ahx_Palm). 162. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-161, wherein X12 is absent, or Ala. 163. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-161, wherein X12 is absent. 164. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-161, wherein X12 is Ala. 165. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-164, wherein X13 is absent. 166. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-165, wherein X14 is absent. 167. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is NH2. 168. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is substituted amino. 169. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is N-alkylamino. 170. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is N-alkylamino, wherein alkyl is further substituted or unsubstitued. 171. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is N-alkylamino, wherein alkyl is further substituted aryl or heteroaryl. 172. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is alkylamino, wherein alkyl is is unsubstituted or substituted with aryl; and alkyl is ethyl, propyl, butyl, or pentyl. 173. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is alkylamino, wherein alkyl is is unsubstituted or substituted with phenyl; and alkyl is ethyl, propyl, butyl, or pentyl. 174. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-166, wherein R2 is OH. 175. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-174, wherein R1 is C1-C20 alkanoyl. 176. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-174, wherein R1 is IVA or isovaleric acid. 177. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-176, wherein the peptide is a linear peptide. 178. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-176, wherein the peptide is a lactam. 179. The hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-176, wherein the peptide is a lactam, wherein any free -NH2 is cyclized with any free -C(O)2H. 180. A hepcidin analogue or pharmaceutically acceptable salt or solvate thereof comprising or consisting of a peptide, wherein the peptide is any one of the peptides listed in Tables 6A-C. 181. A hepcidin analogue or pharmaceutically acceptable salt or solvate thereof comprising or consisting of a peptide, wherein the peptide is ID # 321 ; ID H2 O NH2 ; ID # 322 ; I H2 O O O NH2 ; ID # 320 ; ID ; ID # 286 ; ID ; ID # 287 ; I ; or ID # 292 H2 ; 182. A polynucleotide encoding the peptide present in the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-181. 183. A vector comprising the polynucleotide of claim 182. 184. A pharmaceutical composition comprising the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of any one of claims 1-181, the polynucleotide of claim 182, or the vector of claim 86, and a pharmaceutically acceptable carrier, excipient or vehicle. 185. 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 any one of claims 1-181, or the pharmaceutical composition of claim 184. 186. A method for treating a disease of iron metabolism in a subject in need thereof comprising providing to the subject an effective amount of the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of any one of claims 1-181 or the pharmaceutical composition of claim 184. 187. A method for treating a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof comprising providing to the subject an effective amount of the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof of any one of claims 1-181 or the pharmaceutical composition of claim 184. 188. The method of claim 186 or claim 187, 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. 189. The method of claim 188, wherein the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration. 190. The method of any one of claims 186-189, wherein the disease or disorder is a disease of iron metabolism. 191. The method of claim 190, wherein the disease of iron metabolism is an iron overload disease. 192. The method of any one of claims 186-189, wherein the disease or disorder is a hemochromatosis, a thalassemia, or a polycythemia vera. 193. The method of any one of claims 186-192, wherein the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof or 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. 194. The method of any one of claims 186-192, wherein the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition is provided to the subject at a dosage of about 1 mg to about 100 mg. 195. A device comprising the pharmaceutical composition of claim 184, for delivery of the hepcidin analogue or pharmaceutically acceptable salt or solvate thereof to a subject, optionally orally or subcutaneously. 196. A kit comprising the pharmaceutical composition of claim 184, packaged with a reagent, a device, or an instructional material, or a combination thereof. |
; ID H 2 O NH 2 ; ID # 322
; I H 2 O O O NH 2 ; ID # 320
; ID ; ID # 286 ; ID ; ID # 287
; I ; or ID # 292
H 2 ; [00295] In a particular embodiment, the peptide is any one of peptides wherein the FPN activity is <100 nM. In another particular embodiment, the peptide is any one of peptides wherein the FPN activity is <50 nM. In another particular embodiment, the peptide is any one of peptides wherein the FPN activity is <20 nM. In another particular embodiment, the peptide is any one of peptides wherein the FPN activity is <10 nM. In more particular embodiment, the peptide is any one of peptides wherein the FPN activity is <5 nM. Peptide Analogue Conjugates [00296] In certain embodiments, hepcidin analogues of the present invention, including both monomers and dimers, comprise one or more conjugated chemical substituents, such as lipophilic substituents and polymeric moieties, collectively referred to herein as half-life extension moieties. Without wishing to be bound by any particular theory, it is believed that the lipophilic substituent binds to albumin in the bloodstream, thereby shielding the hepcidin analogue from enzymatic degradation, and thus enhancing its half-life. In addition, it is believed that polymeric moieties enhance half-life and reduce clearance in the bloodstream, and in some cases enhance permeability through the epithelium and retention in the lamina propria. Moreover, it is also surmised that these substituents in some cases may enhance permeability through the epithelium and retention in the lamina propria. The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the invention. For examples of non-limiting suitable chemistry, see, e.g., WO98/08871, WO00/55184, WO00/55119, Madsen et al (J. Med. Chem.2007, 50, 6126-32), and Knudsen et al.2000 (J. Med Chem.43, 1664-1669). [00297] In one embodiment, the side chains of one or more amino acid residues (e.g., Lys residues) in a hepcidin analogue of the invention is further conjugated (e.g., covalently attached) to a lipophilic substituent or other half-life extension moiety. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain, or alternatively may be conjugated to the amino acid side chain via one or more spacers or linker moieties. The spacer or linker moiety, when present, may provide spacing between the hepcidin analogue and the lipophilic substituent. [00298] In certain embodiments, the lipophilic substituent or half-life extension moiety comprises a hydrocarbon chain having from 4 to 30 C atoms, for example at least 8 or 12 C atoms, and preferably 24 C atoms or fewer, or 20 C atoms or fewer. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety which forms part of the attachment to the amino acid side chain or the spacer, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group, and accordingly the hydrocarbon chain may form part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl. [00299] A lipophilic substituent may be conjugated to any amino acid side chain in a hepcidin analogue of the invention In certain embodiment the amino acid side chain includes a carboxy, hydroxyl, thiol, amide or amine group, for forming an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide with the spacer or lipophilic substituent. For example, the lipophilic substituent may be conjugated to Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn. In certain embodiments, the lipophilic substituent is conjugated to Lys. An amino acid shown as Lys in any of the formula provided herein may be replaced by, e.g., Dbu, Dpr or Orn where a lipophilic substituent is added. [00300] In further embodiments of the present invention, alternatively or additionally, the side-chains of one or more amino acid residues in a hepcidin analogue of the invention may be conjugated to a polymeric moiety or other half-life extension moiety, for example, in order to increase solubility and/or half-life in vivo (e.g., in plasma) and/or bioavailability. Such modifications are also known to reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides. [00301] As used herein, “Polyethylene glycol” or “PEG” is a polyether compound of general formula H-(O-CH2-CH2)n-OH. PEGs are also known as polyethylene oxides (PEOs) or polyoxyethylenes (POEs), depending on their molecular weight PEO, PEE, or POG, as used herein, refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 g/mol, PEO to polymers with a molecular mass above 20,000 g/mol, and POE to a polymer of any molecular mass. PEG and PEO are liquids or low-melting solids, depending on their molecular weights. Throughout this disclosure, the 3 names are used indistinguishably. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g/mol to 10,000,000 g/mol. While PEG and PEO with different molecular weights find use in different applications, and have different physical properties (e.g., viscosity) due to chain length effects, their chemical properties are nearly identical. The polymeric moiety is preferably water-soluble (amphiphilic or hydrophilic), non- toxic, and pharmaceutically inert. Suitable polymeric moieties include polyethylene glycols (PEG), homo- or co-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also encompassed are PEGs that are prepared for purpose of half-life extension, for example, mono-activated, alkoxy-terminated polyalkylene oxides (POA’s) such as mono-methoxy- terminated polyethyelene glycols (mPEG’s); bis activated polyethylene oxides (glycols) or other PEG derivatives are also contemplated Suitable polymers will vary substantially by weights ranging from about 200 to about 40,000 are usually selected for the purposes of the present invention. In certain embodiments, PEGs having molecular weights from 200 to 2,000 daltons or from 200 to 500 daltons are used. Different forms of PEG may also be used, depending on the initiator used for the polymerization process, e.g., a common initiator is a monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated mPEG. Other suitable initiators are known in the art and are suitable for use in the present invention. [00302] Lower-molecular-weight PEGs are also available as pure oligomers, referred to as monodisperse, uniform, or discrete. These are used in certain embodiments of the present invention. [00303] PEGs are also available with different geometries: branched PEGs have three to ten PEG chains emanating from a central core group; star PEGs have 10 to 100 PEG chains emanating from a central core group; and comb PEGs have multiple PEG chains normally grafted onto a polymer backbone. PEGs can also be linear. The numbers that are often included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n = 9 would have an average molecular weight of approximately 400 daltons, and would be labeled PEG 400. [00304] As used herein, “PEGylation” is the act of coupling (e.g., covalently) a PEG structure to the hepcidin analogue of the invention, which is in certain embodiments referred to as a “PEGylated hepcidin analogue”. In certain embodiments, the PEG of the PEGylated side chain is a PEG with a molecular weight from about 200 to about 40,000. In certain embodiments, the PEG portion of the conjugated half-life extension moiety is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In particular embodiments, it is PEG11. In certain embodiments, the PEG of a PEGylated spacer is PEG3 or PEG8. In some embodiments, a spacer is PEGylated. In certain embodiments, the PEG of a PEGylated spacer is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of a PEGylated spacer is PEG3 or PEG8. [00305] In some embodiments, the present invention includes a hepcidin analogue peptide (or a dimer thereof) conjugated with a PEG that is attached covalently, e.g., through an amide, a thiol, via click chemistry, or via any other suitable means known in the art. In particular embodiments PEG is attached through an amide bond and, as such, certain PEG derivatives used will be appropriately functionalized. For example, in certain embodiments, PEG11, which is O-(2-aminoethyl)-O′-(2-carboxyethyl)-undecaethyleneglycol, has both an amine and carboxylic acid for attachment to a peptide of the present invention. In certain embodiments, PEG25 contains a diacid and 25 glycol moieties. [00306] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, poly-aspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995), Bioconjugate Chem., vol.6: 332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol.3, 49- 57 and Tsukada, et al. (1984), J. Natl. Cancer Inst., vol.73, : 721-729. The polymeric moiety may be straight-chain or branched. In some embodiments, it has a molecular weight of 500- 40,000 Da, for example 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da. [00307] In some embodiments, a hepcidin analogue of the invention may comprise two or more such polymeric moieties, in which case the total molecular weight of all such moieties will generally fall within the ranges provided above. [00308] In some embodiments, the polymeric moiety may be coupled (by covalent linkage) to an amino, carboxyl or thiol group of an amino acid side chain. Certain examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, and the carboxyl groups of Asp and Glu residues may also be involved. [00309] The skilled worker will be well aware of suitable techniques which can be used to perform the coupling reaction. For example, a PEG moiety bearing a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using reagents commercially available from Nektar Therapeutics AL. See also WO 2008/101017, and the references cited above, for details of suitable chemistry. A maleimide-functionalised PEG may also be conjugated to the side-chain sulfhydryl group of a Cys residue. [00310] As used herein, disulfide bond oxidation can occur within a single step or is a two-step process. As used herein, for a single oxidation step, the trityl protecting group is often employed during assembly, allowing deprotection during cleavage, followed by solution oxidation. When a second disulfide bond is required, one has the option of native or selective oxidation. For selective oxidation requiring orthogonal protecting groups, Acm and Trityl is used as the protecting groups for cysteine. Cleavage results in the removal of one protecting pair of cysteine allowing oxidation of this pair. The second oxidative deprotection step of the cysteine protected Acm group is then performed. For native oxidation, the trityl protecting group is used for all cysteines, allowing for natural folding of the peptide. [00311] A skilled worker will be well aware of suitable techniques which can be used to perform the oxidation step [00312] In particular embodiments, a hepcidin analogue of the present invention comprises a half-life extension moiety, which may be selected from but is not limited to the following: Ahx-Palm, PEG2-Palm, PEG11-Palm, isoGlu-Palm, dapa-Palm, isoGlu-Lauric acid, isoGlu-Mysteric acid, and isoGlu-Isovaleric acid. [00313] In particular embodiments, a hepcidin analogue comprises a half-life extension moiety having the structure shown below, wherein n=0 to 24 or n=14 to 24: . [00314] In certain embodiments, a hepcidin analogue of the present invention comprises a conjugated half-life extension moiety shown in Table 2. Table 2. Illustrative Half-Life Extension Moieties
[00315] In certain embodiments, a half-life extension moiety is conjugated directly to a hepcidin analogue, while in other embodiments, a half-life extension moiety is conjugated to a hepcidin analogue peptide via a linker moiety, e.g., any of those depicted in Table 3. Table 3. Illustrative Linker Moieties*
)
) *(Peg) is –(OCH2CH2)- [00316] With reference to linker structures shown in Table 3, reference to n=1 to 24 or n= 1 to 25, or the like, (e.g., in L4, or L5) indicates that n may be any integer within the recited range. Additional linker moieties can be used are shown in “Abbreviation” table. [00317] In particular embodiments, a hepcidin analogue of the present invention comprises any of the linker moieties shown in Table 3 and any of the half-life extension moieties shown in Table 2, including any of the following combinations shown in Table 4. Table 4. Illustrative Combinations of Linkers and Half-Life Extension Moieties in Hepcidin Analogues Linker Half-Life Linker Half-Life Linker Half-Life L
Linker Half-Life Linker Half-Life Linker Half-Life L
Linker Half-Life Linker Half-Life Linker Half-Life L
Linker Half-Life Linker Half-Life Linker Half-Life L [00318] In certain embodiments, a hepcidin analogue comprises two or more linkers. In particular embodiments, the two or more linkers are concatamerized, i.e., bound to each other. [00319] In related embodiments, the present invention includes polynucleotides that encode a polypeptide having a peptide sequence present in any of the hepcidin analogues described herein. [00320] In addition, the present invention includes vectors, e.g., expression vectors, comprising a polynucleotide of the present invention. Methods of Treatment [00321] In some embodiments, the present invention provides methods for treating a subject afflicted with a disease or disorder associated with dysregulated hepcidin signaling, wherein the method comprises administering to the subject a hepcidin analogue of the present invention. In some embodiments, the hepcidin analogue that is administered to the subject is present in a composition (e.g., a pharmaceutical composition). In one embodiment, a method is provided for treating a subject afflicted with a disease or disorder characterized by increased activity or expression of ferroportin, wherein the method comprises administering to the individual a hepcidin analogue or composition of the present invention in an amount sufficient to (partially or fully) bind to and agonize ferroportin or mimic hepcidin in the subject. In one embodiment, a method is provided for treating a subject afflicted with a disease or disorder characterized by dysregulated iron metabolism, wherein the method comprises administering to the subject a hepcidin analogue or composition of the present invention. [00322] In some embodiments, methods of the present invention comprise providing a hepcidin analogue or a composition of the present invention to a subject in need thereof. In particular embodiments, the subject in need thereof has been diagnosed with or has been determined to be at risk of developing a disease or disorder characterized by dysregulated iron levels (e.g., diseases or disorders of iron metabolism; diseases or disorders related to iron overload; and diseases or disorders related to abnormal hepcidin activity or expression). In particular embodiments, the subject is a mammal (e.g., a human). [00323] In certain embodiments, the disease or disorder is a disease of iron metabolism, such as, e.g., an iron overload disease, iron deficiency disorder, disorder of iron biodistribution, or another disorder of iron metabolism and other disorder potentially related to iron metabolism, etc. In particular embodiments, the disease of iron metabolism is hemochromatosis, 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, thalassemia, thalassemia intermedia, alpha thalassemia, beta thalassemia, sideroblastic anemia, porphyria, porphyria cutanea tarda, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia, hypochromic microcytic anemia, sickle cell disease, polycythemia vera (primary and secondary), secondary erythrocytoses, such as Chronic obstructive pulmonary disease (COPD), post-renal transplant, Chuvash, HIF and PHD mutations and idiopathic myelodysplasia pyruvate kinase deficiency hypochromic microcytic anemia, transfusion-dependent anemia, hemolytic anemia, iron deficiency of obesity, other anemias, benign or malignant tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer (e.g., liver cancer), hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, dementia, multiple sclerosis, Parkinson's disease, Huntington's disease, or Alzheimer's disease. [00324] In certain embodiments, the disease or disorder is related to iron overload diseases such as iron hemochromatosis, 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, thalassemia, thalassemia intermedia, alpha thalassemia, sickle cell disease, myelodysplasia, sideroblastic infections, diabetic retinopathy, and pyruvate kinase deficiency. [00325] In certain embodiments, the disease or disorder is one that is not typically identified as being iron related. For example, hepcidin is highly expressed in the murine pancreas suggesting that diabetes (Type I or Type II), insulin resistance, glucose intolerance and other disorders may be ameliorated by treating underlying iron metabolism disorders. See Ilyin, G. et al. (2003) FEBS Lett. 54222-26, which is herein incorporated by reference. As such, peptides of the invention may be used to treat these diseases and conditions. Those skilled in the art are readily able to determine whether a given disease can be treated with a peptide according to the present invention using methods known in the art, including the assays of WO 2004092405, which is herein incorporated by reference, and assays which monitor hepcidin, hemojuvelin, or iron levels and expression, which are known in the art such as those described in U.S. Patent No.7,534,764, which is herein incorporated by reference. [00326] In certain embodiments, the disease or disorder is postmenopausal osteoporosis. [00327] In certain embodiments of the present invention, the diseases of iron metabolism are iron overload diseases, which include hereditary hemochromatosis, iron-loading anemias, alcoholic liver diseases, heart disease and/or failure, cardiomyopathy, and chronic hepatitis C. [00328] In particular embodiments, any of these diseases, disorders, or indications are caused by or associated with a deficiency of hepcidin or iron overload. [00329] In some embodiments, methods of the present invention comprise providing a hepcidin analogue of the present invention (ie a first therapeutic agent) to a subject in need thereof in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject before and/or simultaneously with and/or after the pharmaceutical composition is administered to the subject. In particular embodiments, the second therapeutic agent is iron chelator. In certain embodiments, the second therapeutic agent is selected from the iron chelators Deferoxamine and Deferasirox (Exjade ™). In another embodiment, the method comprises administering to the subject a third therapeutic agent. [00330] The present invention provides compositions (for example pharmaceutical compositions) comprising one or more hepcidin analogues of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutically acceptable carrier, diluent or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. [00331] The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3- aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for use in animals, including humans. [00332] In certain embodiments, the compositions comprise two or more hepcidin analogues disclosed herein. In certain embodiments, the combination is selected from one of the following: (i) any two or more of the hepcidin analogue peptide monomers shown therein; (ii) any two or more of the hepcidin analogue peptide dimers disclosed herein; (iii) any one or more of the hepcidin analogue peptide monomers disclosed herein, and any one or more of the hepcidin analogue peptide dimers disclosed herein. [00333] It is to be understood that the inclusion of a hepcidin analogue of the invention (ie one or more hepcidin analogue peptide monomers of the invention or one or more hepcidin analogue peptide dimers of the present invention) in a pharmaceutical composition also encompasses inclusion of a pharmaceutically acceptable salt or solvate of a hepcidin analogue of the invention. In particular embodiments, the pharmaceutical compositions further comprise one or more pharmaceutically acceptable carrier, excipient, or vehicle. [00334] In certain embodiments, the invention provides a pharmaceutical composition comprising a hepcidin analogue, or a pharmaceutically acceptable salt or solvate thereof, for treating a variety of conditions, diseases, or disorders as disclosed herein or elsewhere (see, e.g., Methods of Treatment, herein). In particular embodiments, the invention provides a pharmaceutical composition comprising a hepcidin analogue peptide monomer, or a pharmaceutically acceptable salt or solvate thereof, for treating a variety of conditions, diseases, or disorders as disclosed herein elsewhere (see, e.g., Methods of Treatment, herein). In particular embodiments, the invention provides a pharmaceutical composition comprising a hepcidin analogue peptide dimer, or a pharmaceutically acceptable salt or solvate thereof, for treating a variety of conditions, diseases, or disorders as disclosed herein. [00335] The hepcidin analogues of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one hepcidin analogue of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle. [00336] In some embodiments, the hepcidin analogue pharmaceutical compositions of the invention are in unit dosage form. In such forms, the composition is divided into unit doses containing appropriate quantities of the active component or components. The unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of these packaged forms. A unit dosage form may also be provided in single- dose injectable form, for example in the form of a pen device containing a liquid-phase (typically aqueous) composition. Compositions may be formulated for any suitable route and means of administration, e.g., any one of the routes and means of administration disclosed herein. [00337] In particular embodiments, the hepcidin analogue, or the pharmaceutical composition comprising a hepcidin analogue, is suspended in a sustained-release matrix. A sustained-release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. One embodiment of a biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid). [00338] In certain embodiments, the compositions are administered parenterally, subcutaneously or orally. In particular embodiments, the compositions are administered orally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch, including delivery intravitreally, intranasally, and via inhalation) or buccally. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intra-articular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration. [00339] In certain embodiments, pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, beta- cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of an injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. [00340] Injectable depot forms include those made by forming microencapsule matrices of the hepcidin analogue in one or more biodegradable polymers such as polylactide- polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG. Depending upon the ratio of peptide to polymer and the nature of the particular polymer employed, the rate of release of the hepcidin analogue can be controlled. Depot injectable formulations are also prepared by entrapping the hepcidin analogue in liposomes or microemulsions compatible with body tissues. [00341] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. [00342] Hepcidin analogues of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi- lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a hepcidin analogue of the present invention, stabilizers, preservatives, excipients, and the like. In certain embodiments, the lipids comprise phospholipids, including the phosphatidyl cholines (lecithins) and serines, both natural and synthetic. Methods to form liposomes are known in the art. [00343] Pharmaceutical compositions to be used in the invention suitable for parenteral administration may comprise sterile aqueous solutions and/or suspensions of the peptide inhibitors made isotonic with the blood of the recipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like. [00344] In some aspects, the invention provides a pharmaceutical composition for oral delivery. Compositions and hepcidin analogues of the instant invention may be prepared for oral administration according to any of the methods, techniques, and/or delivery vehicles described herein. Further, one having skill in the art will appreciate that the hepcidin analogues of the instant invention may be modified or integrated into a system or delivery vehicle that is not disclosed herein, yet is well known in the art and compatible for use in oral delivery of peptides. [00345] In certain embodiments, formulations for oral administration may comprise adjuvants (e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls and/or enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation. In certain embodiments, the hepcidin analogue of a solid-type dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha- tocopherol, antioxidants such as cysteine, disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening agents, flavoring agents or perfuming agents. [00346] In particular embodiments, oral dosage forms or unit doses compatible for use with the hepcidin analogues of the present invention may include a mixture of hepcidin analogue and nondrug components or excipients, as well as other non-reusable materials that may be considered either as an ingredient or packaging. Oral compositions may include at least one of a liquid, a solid, and a semi-solid dosage forms. In some embodiments, an oral dosage form is provided comprising an effective amount of hepcidin analogue, wherein the dosage form comprises at least one of a pill, a tablet, a capsule, a gel, a paste, a drink, a syrup, ointment, and suppository. In some instances, an oral dosage form is provided that is designed and configured to achieve delayed release of the hepcidin analogue in the subject’s small intestine and/or colon. [00347] In one embodiment, an oral pharmaceutical composition comprising a hepcidin analogue of the present invention comprises an enteric coating that is designed to delay release of the hepcidin analogue in the small intestine. In at least some embodiments, a pharmaceutical composition is provided which comprises a hepcidin analogue of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. In some instances, pharmaceutical compositions of the instant invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition is provided comprising an enteric coating comprising a polymer having dissociable carboxylic groups, such as derivatives of cellulose, including hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar derivatives of cellulose and other carbohydrate polymers. [00348] In one embodiment, a pharmaceutical composition comprising a hepcidin analogue of the present invention is provided in an enteric coating the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the subject’s lower gastrointestinal system, and to avoid systemic side effects. In addition to enteric coatings, the hepcidin analogues of the instant invention may be encapsulated, coated, engaged or otherwise associated within any compatible oral drug delivery system or component. For example, in some embodiments a hepcidin analogue of the present invention is provided in a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems. [00349] To overcome peptide degradation in the small intestine, some embodiments of the present invention comprise a hydrogel polymer carrier system in which a hepcidin analogue of the present invention is contained, whereby the hydrogel polymer protects the hepcidin analogue from proteolysis in the small intestine and/or colon. The hepcidin analogues of the present invention may further be formulated for compatible use with a carrier system that is designed to increase the dissolution kinetics and enhance intestinal absorption of the peptide. These methods include the use of liposomes, micelles and nanoparticles to increase GI tract permeation of peptides. [00350] Various bioresponsive systems may also be combined with one or more hepcidin analogue of the present invention to provide a pharmaceutical agent for oral delivery. In some embodiments, a hepcidin analogue of the instant invention is used in combination with a bioresponsive system, such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan and alginate) to provide a therapeutic agent for oral administration. Other embodiments include a method for optimizing or prolonging drug residence time for a hepcidin analogue disclosed herein, wherein the surface of the hepcidin analogue surface is modified to comprise mucoadhesive properties through hydrogen bonds, polymers with linked mucins or/and hydrophobic interactions. These modified peptide molecules may demonstrate increase drug residence time within the subject, in accordance with a desired feature of the invention. Moreover, targeted mucoadhesive systems may specifically bind to receptors at the enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing the hepcidin analogue. [00351] Other embodiments comprise a method for oral delivery of a hepcidin analogue of the present invention, wherein the hepcidin analogue is provided to a subject in combination with permeation enhancers that promote the transport of the peptides across the intestinal mucosa by increasing paracellular or transcellular permeation For example in one embodiment, a permeation enhancer is combined with a hepcidin analogue, wherein the permeation enhancer comprises at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In one embodiment, a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with the hepcidin analogue of the instant invention, wherein the permeation enhancer favors membrane transport and further dissociation once reaching the blood circulation. In another embodiment, a hepcidin analogue of the present invention is conjugated to oligoarginine, thereby increasing cellular penetration of the peptide into various cell types. Further, in at least one embodiment a noncovalent bond is provided between a peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the hepcidin analogue molecule. [00352] Other embodiments of the invention provide a method for treating a subject with a hepcidin analogue of the present invention having an increased half-life. In one aspect, the present invention provides a hepcidin analogue having a half-life of at least several hours to one day in vitro or in vivo (e.g., when administered to a human subject) sufficient for daily (q.d.) or twice daily (b.i.d.) dosing of a therapeutically effective amount. In another embodiment, the hepcidin analogue has a half-life of three days or longer sufficient for weekly (q.w.) dosing of a therapeutically effective amount. Further, in another embodiment, the hepcidin analogue has a half-life of eight days or longer sufficient for bi-weekly (b.i.w.) or monthly dosing of a therapeutically effective amount. In another embodiment, the hepcidin analogue is derivatized or modified such that is has a longer half-life as compared to the underivatized or unmodified hepcidin analogue. In another embodiment, the hepcidin analogue contains one or more chemical modifications to increase serum half-life. [00353] When used in at least one of the treatments or delivery systems described herein, a hepcidin analogue of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form. Dosages [00354] The total daily usage of the hepcidin analogues and compositions of the present invention can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific hepcidin analogue employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the specific hepcidin analogue employed, and like factors well known in the medical arts. [00355] In particular embodiments, the total daily dose of the hepcidin analogues of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily or 1 to 300 mg/kg body weight daily. In certain embodiments, a dosage of a hepcidin analogue of the present invention is in the range from about 0.0001 to about 100 mg/kg body weight per day, such as from about 0.0005 to about 50 mg/kg body weight per day, such as from about 0.001 to about 10 mg/kg body weight per day, e.g. from about 0.01 to about 1 mg/kg body weight per day, administered in one or more doses, such as from one to three doses. In particular embodiments, a total dosage is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg about once or twice weekly, e.g., for a human patient. In particular embodiments, the total dosage is in the range of about 1 mg to about 5 mg, or about 1 mg to about 3 mg, or about 2 mg to about 3 mg per human patient, e.g., about once weekly. [00356] In various embodiments, a hepcidin analogue of the invention may be administered continuously (e.g. by intravenous administration or another continuous drug administration method), or may be administered to a subject at intervals, typically at regular time intervals, depending on the desired dosage and the pharmaceutical composition selected by the skilled practitioner for the particular subject. Regular administration dosing intervals include, e.g., once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, and the like. [00357] Such regular hepcidin analogue administration regimens of the invention may, in certain circumstances such as, e.g., during chronic long-term administration, be advantageously interrupted for a period of time so that the medicated subject reduces the level of or stops taking the medication, often referred to as taking a “drug holiday.” Drug holidays are useful for, e.g., maintaining or regaining sensitivity to a drug especially during long-term chronic treatment, or to reduce unwanted side-effects of long-term chronic treatment of the subject with the drug. The timing of a drug holiday depends on the timing of the regular dosing regimen and the purpose for taking the drug holiday (e.g., to regain drug sensitivity and/or to reduce unwanted side effects of continuous long- term administration) In some embodiments the drug holiday may be a reduction in the dosage of the drug (e.g. to below the therapeutically effective amount for a certain interval of time). In other embodiments, administration of the drug is stopped for a certain interval of time before administration is started again using the same or a different dosing regimen (e.g. at a lower or higher dose and/or frequency of administration). A drug holiday of the invention may thus be selected from a wide range of time-periods and dosage regimens. An exemplary drug holiday is two or more days, one or more weeks, or one or more months, up to about 24 months of drug holiday. So, for example, a regular daily dosing regimen with a peptide, a peptide analogue, or a dimer of the invention may, for example, be interrupted by a drug holiday of a week, or two weeks, or four weeks, after which time the preceding, regular dosage regimen (e.g. a daily or a weekly dosing regimen) is resumed. A variety of other drug holiday regimens are envisioned to be useful for administering the hepcidin analogues of the invention. [00358] Thus, the hepcidin analogues may be delivered via an administration regime which comprises two or more administration phases separated by respective drug holiday phases. [00359] During each administration phase, the hepcidin analogue is administered to the recipient subject in a therapeutically effective amount according to a pre-determined administration pattern. The administration pattern may comprise continuous administration of the drug to the recipient subject over the duration of the administration phase. Alternatively, the administration pattern may comprise administration of a plurality of doses of the hepcidin analogue to the recipient subject, wherein said doses are spaced by dosing intervals. [00360] A dosing pattern may comprise at least two doses per administration phase, at least five doses per administration phase, at least 10 doses per administration phase, at least 20 doses per administration phase, at least 30 doses per administration phase, or more. [00361] Said dosing intervals may be regular dosing intervals, which may be as set out above, including once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, or a regular and even less frequent dosing interval, depending on the particular dosage formulation, bioavailability, and pharmacokinetic profile of the hepcidin analogue of the present invention. [00362] An administration phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more. [00363] Where an administration pattern comprises a plurality of doses, the duration of the following drug holiday phase is longer than the dosing interval used in that administration pattern. Where the dosing interval is irregular, the duration of the drug holiday phase may be greater than the mean interval between doses over the course of the administration phase. Alternatively the duration of the drug holiday may be longer than the longest interval between consecutive doses during the administration phase. [00364] The duration of the drug holiday phase may be at least twice that of the relevant dosing interval (or mean thereof), at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times that of the relevant dosing interval or mean thereof. [00365] Within these constraints, a drug holiday phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more, depending on the administration pattern during the previous administration phase. [00366] An administration regime comprises at least 2 administration phases. Consecutive administration phases are separated by respective drug holiday phases. Thus the administration regime may comprise at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 administration phases, or more, each separated by respective drug holiday phases. [00367] Consecutive administration phases may utilise the same administration pattern, although this may not always be desirable or necessary. However, if other drugs or active agents are administered in combination with a hepcidin analogue of the invention, then typically the same combination of drugs or active agents is given in consecutive administration phases. In certain embodiments, the recipient subject is human. [00368] In some embodiments, the present invention provides compositions and medicaments comprising at least one hepcidin analogue as disclosed herein. In some embodiments, the present invention provides a method of manufacturing medicaments comprising at least one hepcidin analogue as disclosed herein for the treatment of diseases of iron metabolism, such as iron overload diseases. In some embodiments, the present invention provides a method of manufacturing medicaments comprising at least one hepcidin analogue as disclosed herein for the treatment of diabetes (Type I or Type II), insulin resistance, or glucose intolerance. Also provided are methods of treating a disease of iron metabolism in a subject, such as a mammalian subject, and preferably a human subject, comprising administering at least one hepcidin analogue or composition as disclosed herein to the subject In some embodiments, the hepcidin analogue or the composition is administered in a therapeutically effective amount. Also provided are methods of treating diabetes (Type I or Type II), insulin resistance, or glucose intolerance in a subject, such as a mammalian subject, and preferably a human subject, comprising administering at least one hepcidin analogue or composition as disclosed herein to the subject. In some embodiments, the hepcidin analogue or composition is administered in a therapeutically effective amount. [00369] In some embodiments, the invention provides a process for manufacturing a hepcidin analogue or a hepcidin analogue composition (e.g., a pharmaceutical composition), as disclosed herein. [00370] In some embodiments, the invention provides a device comprising at least one hepcidin analogue of the present invention, or pharmaceutically acceptable salt or solvate thereof for delivery of the hepcidin analogue to a subject. [00371] In some embodiments, the present invention provides methods of binding a ferroportin or inducing ferroportin internalization and degradation which comprises contacting the ferroportin with at least one hepcidin analogue, or hepcidin analogue composition as disclosed herein. [00372] In some embodiments, the present invention provides methods of binding a ferroportin to block the pore and exporter function without causing ferroportin internalization. Such methods comprise contacting the ferroportin with at least one hepcidin analogue, or hepcidin analogue composition as disclosed herein. [00373] In some embodiments, the present invention provides kits comprising at least one hepcidin analogue, or hepcidin analogue composition (e.g., pharmaceutical composition) as disclosed herein packaged together with a reagent, a device, instructional material, or a combination thereof. [00374] In some embodiments, the present invention provides a method of administering a hepcidin analogue or hepcidin analogue composition (e.g., pharmaceutical composition) of the present invention to a subject via implant or osmotic pump, by cartridge or micro pump, or by other means appreciated by the skilled artisan, as well-known in the art. In some embodiments, the present invention provides complexes which comprise at least one hepcidin analogue as disclosed herein bound to a ferroportin, preferably a human ferroportin, or an antibody, such as an antibody which specifically binds a hepcidin analogue as disclosed herein, Hep25, or a combination thereof. [00375] In some embodiments, the hepcidin analogue of the present invention has a measurement (e.g., an EC50) of less than 500 nM within the FPN internalization assay. As a skilled person will realize, the function of the hepcidin analogue is dependent on the tertiary structure of the hepcidin analogue and the binding surface presented. It is therefore possible to make minor changes to the sequence encoding the hepcidin analogue that do not affect the fold or are not on the binding surface and maintain function. In other embodiments, the present invention provides a hepcidin analogue having 85% or higher (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%) identity or homology to an amino acid sequence of any hepcidin analogue described herein that exhibits an activity (e.g., hepcidin activity), or lessens a symptom of a disease or indication for which hepcidin is involved. [00376] In other embodiments, the present invention provides a hepcidin analogue having 85% or higher (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%) identity or homology to an amino acid sequence of any hepcidin analogue presented herein, or a peptide according to any one of the formulae or hepcidin analogues described herein. [00377] In some embodiments, a hepcidin analogue of the present invention may comprise functional fragments or variants thereof that have at most 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions compared to one or more of the specific peptide analogue sequences recited herein. [00378] In addition to the methods described in the Examples herein, the hepcidin analogues of the present invention may be produced using methods known in the art including chemical synthesis, biosynthesis or in vitro synthesis using recombinant DNA methods, and solid phase synthesis. See e.g. Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J. K. Setlow ed., Plenum Press, NY, pp. 1-19; Merrifield (1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:5131-5135; and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are herein incorporated by reference. The hepcidin analogues of the present invention may be purified using protein purification techniques known in the art such as reverse phase high-performance liquid chromatography (HPLC), ion-exchange or immunoaffinity chromatography, filtration or size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl (1973) Biochem.12(16):3121-3126; and Scopes (1982) Protein Purification, Springer- Verlag, NY, which are herein incorporated by reference. Alternatively, the hepcidin analogues of the present invention may be made by recombinant DNA techniques known in the art Thus polynucleotides that encode the polypeptides of the present invention are contemplated herein. In certain preferred embodiments, the polynucleotides are isolated. As used herein "isolated polynucleotides" refers to polynucleotides that are in an environment different from that in which the polynucleotide naturally occurs. EXAMPLES [00379] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those of skill in the art, except where otherwise described in detail. It is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions or scope of the invention. As such, they should not be construed in any way as limiting the scope of the present invention. ABBREVIATIONS: DCM: dichloromethane DMF: N,N-dimethylformamide NMP: N-methylpyrolidone HBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate DCC: Dicyclohexylcarbodiimide NHS: N-hydoxysuccinimide DIPEA: diisopropylethylamine EtOH: ethanol Et2O: diethyl ether Hy: hydrogen TFA: trifluoroacetic acid TIS: triisopropylsilane ACN: acetonitrile HPLC: high performance liquid chromatography ESI-MS: electron spray ionization mass spectrometry PBS: phosphate-buffered saline Boc: t-butoxycarbonyl Fmoc: Fluorenylmethyloxycarbonyl Acm: acetamidomethyl IVA: Isovaleric acid (or Isovaleryl) [00380] K( ): In the peptide sequences provided herein, wherein a compound or chemical group is presented in parentheses directly after a Lysine residue, it is to be understood that the compound or chemical group in the parentheses is a side chain conjugated to the Lysine residue. So, e.g., but not to be limited in any way, K-[(PEG8)]- indicates that a PEG8 moiety is conjugated to a side chain of this Lysine. [00381] Palm: Indicates conjugation of a palmitic acid (palmitoyl). SYNTHETIC PROTOCOL -1 SYNTHESIS OF PEPTIDE MONOMERS [00382] Peptide monomers of the present invention were synthesized using the Merrifield solid phase synthesis techniques on Protein Technology’s Symphony multiple channel synthesizer. The peptides were assembled using HBTU (O-Benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions. For some amino acid couplings PyAOP(7-Azabenzotriazol-1- yloxy)tripyrrolidinophosponium hexafluorophosphate) and DIEA conditions were used. Rink Amide MBHA resin (100-200 mesh, 0.57 mmol/g) was used for peptide with C-terminal amides and pre-loaded Wang Resin with N- ^-Fmoc protected amino acid was used for peptide with C-terminal acids. The coupling reagents (HBTU and DIEA premixed) were prepared at 100 mmol concentration. Similarly, amino acids solutions were prepared at 100 mmol concentration. Peptide inhibitors of the present invention were identified based on medical chemistry optimization and/or phage display and screened to identify those having superior binding and/or inhibitory properties. Assembly [00383] The peptides were assembled using standard Symphony protocols. The peptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4ml of DMF followed by treatment with 2.5ml of 20% 4-methyl piperidine (Fmoc de-protection) for 10min. The resin was then filtered and washed two times with DMF (4ml) and re-treated with Piperidine for additional 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition 2.5ml of amino acid and 2.5ml of HBTU-DIEA mixture After 45min of frequent agitations the resin was filtered and washed three timed with DMF (4 ml each). For a typical peptide of the present invention, double couplings were performed. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling. Cleavage [00384] Following completion of the peptide assembly, the peptide was cleaved from the resin by treatment with cleavage reagent, such as reagent K (82.5% trifluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol). The cleavage reagent was able to successfully cleave the peptide from the resin, as well as all remaining side chain protecting groups. [00385] The cleaved peptides were precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrile : water (7:3 with 1% TFA) and filtered. The quality of linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass/Waters ZQ) before being purified. Purification [00386] Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-Preparative reverse phase HPLC was performed on a Gemini 10 μm C18 column (22 mm x 250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 20 mL/min (preparative). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 15mL/min (preparative). SYNTHETIC PROTOCOL -1 SYNTHESIS OF PEPTIDE MONOMERS [00387] Peptide monomers of the present invention were synthesized using standard Fmoc solid phase synthesis techniques on a CEM Liberty Blue TM microwave peptide synthesizer. The peptides were assembled using Oxyma/DIC (ethyl cyanohydroxyiminoacetate / diisopropylcarbodiimide) with microwave heating. Rink Amide-MBHA resin (100-200 mesh, 0.66 mmol/g) was used for peptides with C-terminal amides and pre-loaded Wang Resin with N- ^-Fmoc protected amino acid was used for peptide with C-terminal acids. Oxyma was prepared as a 1M solution in DMF with 0.1M DIEA. DIC was prepared as 0.5M solution in DMF. The Amino acids were prepared at 200mM. Peptide inhibitors of the present invention were identified based on medicinal chemistry optimization and/or phage display and screened to identify those having superior binding and/or inhibitory properties. Assembly [00388] The peptides were made using standard CEM Liberty Blue TM protocols. The peptide sequences were assembled as follows: Resin (400 mg, 0.25 mmol) was suspended in 10 ml of 50/50 DMF/DCM. The resin was then transferred to the reaction vessel in the microwave cavity. The peptide was assembled using repeated Fmoc deprotection and Oxyma/DIC coupling cycles. For deprotection, 20% 4-methylpiperidine in DMF was added to the reaction vessel and heated to 90 o C for 65 seconds. The deprotection solution was drained and the resin washed three times with DMF. For most amino acids, 5 equivalents of amino acid, Oxyma and DIC were then added to the reaction vessel and microwave irradiation rapidly heated the mixing reaction to 90 o C for 4 min. For Arginine and Histidine residues, milder conditions using respective temperatures of 75 and 50 o C for 10 min were used to prevent racemization. Rare and expensive amino acids were often coupled manually overnight at room temperature using only 1.5-2 eq of reagents. Difficult couplings were often double coupled 2 x 4 min at 90 o C. After coupling the resin was washed with DMF and the whole cycle was repeated until the desired peptide assembly was completed. Cleavage [00389] Following completion of the peptide assembly, the peptide was then cleaved from the resin by treatment with a standard cleavage cocktail of 91:5:2:2 TFA/H 2 O/TIPS/DODT for 2 hrs. If more than one Arg(Pbf) residue was present the cleavage was allowed to go for an additional hour. [00390] The cleaved peptides were precipitated in cold diethyl ether. The filtrate was decanted off and a second aliquot of cold ether was added, and the procedure was repeated. The quality of linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Waters® Micromass® ZQ TM ) before being purified. [00391] Purification Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini® C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-Preparative reverse phase HPLC was performed on a Gemini® 10 μm C18 column (22 mm x 250 mm) (Phenomenex) or Jupiter® 10 μm, 300 A º C18 column (21.2 mm x 250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 20 mL/min (preparative). EXAMPLE 1A SYNTHESIS OF PEPTIDE ANALOGUES [00392] Unless otherwise specified, reagents and solvents employed in the following were available commercially in standard laboratory reagent or analytical grade, and were used without further purification. Procedure for solid-phase synthesis of peptides Method A [00393] Peptide analogues of the invention were chemically synthesized using optimized 9-fluorenylmethoxy carbonyl (Fmoc) solid phase peptide synthesis protocols. For C-terminal amides, rink-amide resin was used, although wang and trityl resins were also used to produce C-terminal acids. The side chain protecting groups were as follows: Glu, Thr and Tyr: O-tButyl; Trp and Lys: t-Boc (t-butyloxycarbonyl); Arg: N-gamma-2,2,4,6,7- pentamethyldihydrobenzofuran-5-sulfonyl; His, Gln, Asn, Cys: Trityl. For selective disulfide bridge formation, Acm (acetamidomethyl) was also used as a Cys protecting group. For coupling, a four to ten-fold excess of a solution containing Fmoc amino acid, HBTU and DIEA (1:1:1.1) in DMF was added to swelled resin [HBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate; DIEA: diisopropylethylamine; DMF: dimethylformamide]. HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) was used instead of HBTU to improve coupling efficiency in difficult regions. Fmoc protecting group removal was achieved by treatment with a DMF, piperidine (2:1) solution. Method B [00394] Alternatively, peptides were synthesized utilizing the CEM liberty Blue Microwave assisted peptide synthesizer. Using the Liberty Blue, FMOC deprotection was carried out by addition of 20% 4-methylpiperdine in DMF with 0.1M Oxyma in DMF and then heating to 90 o C using microwave irradiation for 4 min. After DMF washes the FMOC-amino acids were coupled by addition of 0.2M amino acid (4-6 eq), 0.5M DIC (4-6 eq) and 1M Oxyma (with 0.1M DIEA) 4-6 eq (all in DMF). The coupling solution is heated using microwave radiation to 90 o C for 4 min. A second coupling is employed when coupling Arg or other sterically hindered amino acids. When coupling with histidine, the reaction is heated to 50 o C for 10 min. The cycles are repeated until the full length peptide is obtained. Procedure for cleavage of peptides off resin [00395] Side chain deprotection and cleavage of the peptide analogues of the invention (e.g., Compound No. 2) was achieved by stirring dry resin in a solution containing trifluoroacetic acid, water, ethanedithiol and tri-isopropylsilane (90:5:2.5:2.5) for 2 to 4 hours. Following TFA removal, peptide was precipitated using ice-cold diethyl ether. The solution was centrifuged and the ether was decanted, followed by a second diethyl ether wash. The peptide was dissolved in an acetonitrile, water solution (1:1) containing 0.1% TFA (trifluoroacetic acid) and the resulting solution was filtered. The linear peptide quality was assessed using electrospray ionization mass spectrometry (ESI-MS). Procedure for purification of peptides [00396] Purification of the peptides of the invention (e.g., Compound No. 2) was achieved using reverse-phase high performance liquid chromatography (RP-HPLC). Analysis was performed using a C18 column (3µm, 50 x 2mm) with a flow rate of 1 mL/min. Purification of the linear peptides was achieved using preparative RP-HPLC with a C18 column (5µm, 250 x 21.2 mm) with a flow rate of 20 mL/min. Separation was achieved using linear gradients of buffer B in A (Buffer A: Aqueous 0.05% TFA; Buffer B: 0.043% TFA, 90% acetonitrile in water). [00397] One of skill in the art will appreciate that standard methods of peptide synthesis may be used to generate the compounds of the invention. Conjugation of Half-Life Extension Moieties [00398] Conjugation of peptides were performed on resin. Lys(ivDde) was used as the key amino acid. After assembly of the peptide on resin, selective deprotection of the ivDde group occurred using 3 x 5 min 2% hydrazine in DMF for 5 min. Activation and acylation of the linker using HBTU, DIEA 1-2 equivalents for 3 h, and Fmoc removal followed by a second acylation with the lipidic acid gave the conjugated peptide. EXAMPLE 1B SYNTHESIS OF PEPTIDE: Isovaleric acid-Glu-Thr-His-DIP-Pro-Ala-Ile-Lys(Ahx-Palm)- bhF-NH2 (PEPTIDE # 9) [00399] The TFA salt of Peptide #9 was synthesized on a 0.13 mmol scale. Upon completion, 45.31 mg of > 95% pure Peptide #9 was isolated as a white powder, representing an overall yield of 21.5%. [00400] The Peptide Peptide # 9 was synthesized using the Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer and constructed on Rink Amide MBHA (100-200 mesh, 0.66 mmol/g) resin using standard Fmoc protection synthesis conditions. The constructed peptide was isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. The crude precipitate was then purified by RP-HPLC. Lyophilization of pure fractions gave the final product Peptide # 9. Peptide Assembly [00401] Swell Resin: 200 mg of Rink Amide MBHA solid phase resin (0.66 mmol/g loading) was transferred to a 25 mL reaction vessel (for Symphony peptide synthesizer). The resin was swelled with 3.75 mL of DMF (3x10 min). [00402] Step 1: Coupling of FMOC- ^homo-L-Phe-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC- ^homo-L-Phe-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00403] Step 2: Coupling of FMOC-L-Lys(IvDde)-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L-Lys(IvDde)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00404] Step 3: Coupling of FMOC-L-Dpa-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L-Ile- OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00405] Step 4: Coupling of FMOC-L-Ala-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- Ala-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00406] Step 5: Coupling of FMOC-Pro-OH : Deprotection of the Fmoc group was Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-Pro- OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00407] Step 6: Coupling of FMOC-L-DIP-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- DIP-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00408] Step 7: Coupling of FMOC-L-His(Trt)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- His(Trt)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00409] Step 8: Coupling of FMOC-L-Thr(tBu)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- Thr(tBu)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00410] Step 9: Coupling of FMOC-L-Glu(tBu)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- Glu(tBu)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00411] Step 10: Coupling of Isovaleric acid : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL Isovaleric acid in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00412] Step 11: IvDde removal and Coupling of Fmoc-Ahx-OH: The IvDde was removed from the Lys C-terminus of the resin bound peptide using 2-5% hydrazine in DMF (4 x 30 min), followed by a DMF wash. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid Fmoc-Ahx-OH in DMF (200 mM) and 2.0 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00413] Step 12: Coupling of Palmitic acid: Deprotection of the Fmoc group was Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL Isovaleric acid in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00414] Step 13: TFA Cleavage and Ether precipitation: 10 ml of the cleavage cocktail [TFA cleavage cocktail (90/5/2.5/2.5 TFA/water/Tips/DODT) was added to the protected resin bound peptide and shaken for two hours. Cold Diethyl Ether was added forming a white precipitate that was then centrifuged. The ether was decanted to waste and 2 more ether washes of the precipitate were performed. The resulting white precipitate cake was dissolved in acetonitrile / water (7: 3) and filtered before purification. [00415] Step 14: RP-HPLC purification: Semi-Preparative reverse phase HPLC was performed on a Gemini® 10 μm C18 column (22 mm x 250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 20 mL/min (preparative). [00416] Step 15: Final Lyophilization and Analysis: The collected fractions were analyzed by analytical RP-HPLC, and all fractions >95% purity were combined. Lyophilization of the combined fractions gave Peptide # 9 as a white powder with a purity of 97 %. Low resolution LC/MS of purified Peptide # 9 gave 1 charged states of the peptide, M+2/2 of 807.70 and the molecular ion [M+1] of 1613.80. The experimental mass agrees with the theoretical mass of 1614.0 Da [M+1]. EXAMPLE 1C SYNTHESIS OF PEPTIDE: Isovaleric acid-Glu-Thr-His-Dpa-Pro-Ala-Ile-(D)Lys-bhF- Lys(Ahx-Palm)-NH 2 (PEPTIDE # 4) [00417] The TFA salt of Peptide # 4 was synthesized on a 0.13 mmol scale. Upon completion, 27.74 mg of > 95% pure Peptide # 4 was isolated as a white powder, representing an overall yield of 12.2 %. [00418] The Peptide Peptide # 4 was synthesized using the Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer and constructed on Rink Amide MBHA (100-200 mesh, 0.66 mmol/g) resin using standard Fmoc protection synthesis conditions. The constructed peptide was isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. The crude precipitate was then purified by RP-HPLC. Lyophilization of pure fractions gave the final product Peptide # 4. Peptide Assembly [00419] Swell Resin: 200 mg of Rink Amide MBHA solid phase resin (0.66 mmol/g loading) was transferred to a 25 mL reaction vessel (for Symphony peptide synthesizer). The resin was swelled with 3.75 mL of DMF (3x10 min). [00420] Step 1: Coupling of FMOC-L-Lys(IvDde)-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L-Lys(IvDde)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00421] Step 2: Coupling of FMOC- ^homo-L-Phe-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC- ^homo-L-Phe-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00422] Step 3: Coupling of FMOC-D-Lys(Boc)-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-D- Lys(Boc)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00423] Step 4: Coupling of FMOC-L-Ile-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L-Ile- OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00424] Step 5: Coupling of FMOC-L-Ala-OH: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- Ala-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00425] Step 6: Coupling of FMOC-Pro-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-Pro- OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00426] Step 7: Coupling of FMOC-L-Dpa-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- DIP-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00427] Step 8: Coupling of FMOC-L-His(Trt)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- His(Trt)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00428] Step 9: Coupling of FMOC-L-Thr(tBu)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L- Thr(tBu)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00429] Step 10: Coupling of FMOC-L-Glu(tBu)-OH : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid FMOC-L-Glu(tBu)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00430] Step 11: Coupling of Isovaleric acid : Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL Isovaleric acid in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00431] Step 12: IvDde removal and Coupling of Fmoc-Ahx-OH: The IvDde was removed from the Lys C-terminus of the resin bound peptide using 2-5% hydrazine in DMF (4 x 30 min), followed by a DMF wash. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL of amino acid Fmoc-Ahx-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00432] Step 13: Coupling of Palmitic acid: Deprotection of the Fmoc group was accomplished by two treatments with 2.5 ml of 20% piperidine in DMF twice to the swollen Rink Amide resin for 5 and10 min respectively. After deprotection the resin was washed with 3.75 mL of DMF (3x0.1 min) and followed by addition of 2.5 mL Isovaleric acid in DMF (200 mM) and 25 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM) The coupling reaction was mixed for 1hr, filtered and repeated once (double coupling). After completing the coupling reaction, the resin was washed with 6.25 mL of DMF (3x0.1 min) prior to starting the next deprotection/coupling cycle. [00433] Step 14: TFA Cleavage and Ether precipitation: 10 ml of the cleavage cocktail [TFA cleavage cocktail (90/5/2.5/2.5 TFA/water/Tips/DODT) was added to the protected resin bound peptide and shaken for two hours. Cold Diethyl Ether was added forming a white precipitate that was then centrifuged. The ether was decanted to waste and 2 more ether washes of the precipitate were performed. The resulting white precipitate cake was dissolved in acetonitrile / water (7: 3) and filtered before purification. [00434] Step 15: RP-HPLC purification: Semi-Preparative reverse phase HPLC was performed on a Gemini® 10 μm C18 column (22 mm x 250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 20 mL/min (preparative). [00435] Step 16: Final Lyophilization and Analysis: The collected fractions were analyzed by analytical RP-HPLC, and all fractions >95% purity were combined. Lyophilization of the combined fractions gave Peptide # 4 as a white powder with a purity of 97 %. Low resolution LC/MS of purified Peptide # 4 gave 2 charged states of the peptide, M+3/3 of 581.5, M+2/2 of 871.70 and the molecular ion of 1741.90 [M+1]. The experimental mass agrees with the theoretical mass of 1742.09 Da [M+1]. EXAMPLE 2A ACTIVITY OF PEPTIDE ANALOGUES [00436] Peptide analogues were tested in vitro for induction of internalization of the human ferroportin protein. Following internalization, the ferroporin protein is degraded. The assay used (FPN activity assay) measures a decrease in fluorescence of the receptor. [00437] The cDNA encoding the human ferroportin (SLC40A1) was cloned from a cDNA clone from Origene (NM_014585). The DNA encoding the ferroportin was amplified by PCR using primers also encoding terminal restriction sites for subcloning but without the termination codon. The ferroportin receptor was subcloned into a mammalian GFP expression vector containing a neomycin (G418) resistance marker in such that the reading frame of the ferroportin was fused in frame with the GFP protein. The fidelity of the DNA encoding the protein was confirmed by DNA sequencing. HEK293 cells were used for transfection of the ferroportin-GFP receptor expression plasmid. The cells were grown according to standard protocol in growth medium and transfected with the plasmids using Lipofectamine (manufacturer’s protocol, Invitrogen). The cells stably expressing ferroportin-GFP were selected using G418 in the growth medium (in that only cells that have taken up and incorporated the cDNA expression plasmid survive) and sorted several times on a Cytomation MoFlo ™ cell sorter to obtain the GFP-positive cells (488nm/530 nm). The cells were propagated and frozen in aliquots. [00438] To determine activity of the hepcidin analogues (compounds) on the human ferroportin, the cells were incubated in 96 well plates in standard media, without phenol red. Compound was added to desired final concentration for at least 18 hours in the incubator. Following incubation, the remaining GFP-fluorescence was determined either by whole cell GFP fluorescence (Envision plate reader, 485 / 535 filter pair), or by Beckman Coulter Quanta ™ flow cytometer (express as Geometric mean of fluorescence intensity at 485nm/525nm). Compound was added to desired final concentration for at least 18 hours but no more than 24 hours in the incubator. [00439] In certain experiments, reference compounds included native Hepcidin, Mini- Hepcidin, and R1-Mini-Hepcidin, which is an analog of mini-hepcidin. The “RI” in RI-Mini- Hepcidin refers to Retro Inverse. A retro inverse peptide is a peptide with a reversed sequence in all D amino acids. An example is that Hy-Glu-Thr-His-NH2 becomes Hy-DHis-DThr-DGlu- NH 2 . The EC 50 of these reference compounds for ferroportin internalization / degradation was determined according to the FPN activity assay described above. These peptides served as control standards. Table 5. Reference compounds Potency H H H The potency EC 50 values (nM) determined for various peptide analogues of the present invention are provided in Table 6A, Table 6B, and Table 6C. These values were determined as described herein. Compound ID numbers are indicated by “Compd ID,” and reference compounds are indicated by “Ref. Compd.” FPN EC50 values determined from these data are shown in Table 6A, 6B and 6C. T47D (MSA) IC 50 values are shown in Table 6D. Where not shown, data was not yet determined. PRSK-[SAR]-CK-NH2 SEQ FPN EC50 [bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-L-NH2; 4.5 SEQ FPN EC50 [bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-A-NH2; 11 SEQ FPN EC50 [ bhPhe]-[Lys(Ahx Palm)]-NH2; 103 SEQ FPN EC50 cyclized) 184 SEQ FPN EC50 [Lys(Ac)]-[bhPhe]-NH2; 2080 SEQ FPN EC50 N H2; >3000 SEQ FPN EC50 [ Lys(Ahx C10)]-[bhPhe]-NH 2 ; 123 SEQ FPN EC50 [ Lys(Ahx Palm)]-[bhPhe]-NH2; 372 SEQ FPN EC50 [ (D)Lys]-NH2; 732 SEQ FPN EC50 @ free -NH 2 of amino acid and free -C(O) 2 H of amino acid are cyclized to form a lactam [Lys(Ahx_Palm)]-bhF(1:2) SEQ Cyclized @ FPN T47D @ free -NH2 of amino acid and free -C(O)2H of amino acid are cyclized to form a lactam S D ) [Dpa]-P-A-I-[(D)Lys]-[bhPhe]-NH2;2 SEQ Cyclized @ FPN T47D ) [bhPhe]-NH2; SEQ Cyclized @ FPN T47D ) Benzyl_Amine SEQ Cyclized @ FPN T47D ) [Lys(Ahx_Palm)]-[bhPhe]-NH2; SEQ Cyclized @ FPN T47D ) K-NH2; SEQ Cyclized @ FPN T47D ) [ Lys(Ahx Palm)]-N Ethyl Nap SEQ Cyclized @ FPN T47D ) [(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-R-NH2; SEQ Cyclized @ FPN T47D ) [(D)Lys]-NH2; SEQ Cyclized @ FPN T47D ) [Lys(AhxPalm)]-NH2; SEQ Cyclized @ FPN T47D ) [ bhPhe]-[Lys(Ahx Palm)]-R-NH2; SEQ Cyclized @ FPN T47D ) @ free -NH2 of amino acid and free -C(O)2H of amino acid are cyclized to form a lactam; @@ the side-chain C of alanine and C5 of triazole joined together to form a C-C bond Table 6D. Illustrative Hepcidin Analogues S N n 4 4 MeLys(Ahx Palm)]-[bhGly(phenylbutyl)] Seq Sequence IC50: FPN N n 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 MeLys(Ahx_Palm)]-[bhPhe]-NH2 Seq Sequence IC50: FPN N n 4 4 4 4 4 4 EXAMPLE 2C ACTIVITY OF PEPTIDE ANALOGUES [00440] The potency of the peptides in causing ferroportin internalization was evaluated in a T47D cell-based assay. T47D cell line (HTB 133, ATCC) is a human breast carcinoma adherent cell line which endogenously expresses ferroportin. In this internalization assay, the potency of the test peptides was evaluated in presence of serum albumin which is the main protein component in the blood. T47D cells were maintained in RPMI media (containing required amount of fetal bovine serum) and regularly sub-cultured. In preparation for the assay, the cells were seeded in 96-well plates at a density of 80-100k cells per well in 100ul volume and allowed to rest overnight. On the next day, test peptides were first prepared in dilution series (10-point series, starting concentration of ~5µM, typically 3-4xfold dilution steps), all with 0.5% mouse serum albumin (MSA purified from mouse serum; Sigma, A3139). The test peptide dilution series were allowed to incubate at room temperature for 30min. Then the media was aspirated from the 96-well cell plate and test peptide dilution series were added. After 1hr incubation, the media with test peptides was aspirated out and AF647-conjugated detection peptide was added at fixed concentration of 200nM. The AF647-conjugated detection peptide i l ifi d t bi d t f ti d it i t li ti Th ll washed again after a 2hr incubation in preparation for flow cytometry analysis. The Median Fluorescence Intensity (MFI) of the AF647-positive population was measured (after removing dead cells and non-singlets from the analysis). The MFI values were used to generate a dose- response curve and obtain IC50 potencies for the test peptides. The IC50 potencies were calculated by using 4-parameter non-linear fitting function in Graphpad Prism (Table 6D). Table 6D. T47D/MSA data 4 A 5 389 Compd T47D MSA . Compd T47D MSA EXAMPLE 2D LAD2 ACTIVITY OF PEPTIDE ANALOGUES [00441] In anaphylactoid reactions, the main mechanism involves the direct stimulation of mast cells or basophils leading to the release of anaphylactic mediators such as histamine and β-hexosaminidase. A recent study by McNeil et al. (McNeil BD et al., 2015) reported that MrgprX2, a specific membrane receptor on human mast cells, induces anaphylactoid reactions. The LAD2 (Laboratory of Allergic Diseases 2) human mast cell line derived from human mast cell sarcoma/leukemia (Kirshenbaum et al., 2003), is commonly employed to study anaphylactoid reactions because its biological properties are identical to those of primary human mast cells including the overexpression of the MrgprX2 receptor and sensitivity towards degranulating peptides (Kulka et al., 2008). The release of anaphylactic mediators such as β- hexosaminidase, is assessed by fluorometric quantification. [00442] The degranulation potential of hepcidin mimetics were evaluated in the LAD2 cells. On the day of the assay, serial dilutions of compounds were added to LAD2 cells plated at 20000 cells/well in a 96-well plate. After incubation for 30 minutes, the amount of β- hexosaminidase released into the supernatants and in cell lysates was quantified using the fluorogenic substrate 4-methylumbelliferyl-N-acetyl-b-D-glucosaminide. Dose-response curves were generated by plotting the % of β-hexosaminidase release (y-axis) against the concentrations of peptides tested (x-axis). The EC50 values and standard errors were calculated using XLfit 5.5.0.5 based on the following equation: 4 Parameter Sigmoidal Model: f= (A+((B- A)/(1+((C/x)^D)))) where A=Emin, B=Emax, C=EC50 and D=slope. References: McNeil BD et al., Nature, 12, 519 (2015); Kirshenbaum et al. Leukemia Res.27, 677 (2003); Kulka et al. Immunology 123, 398 (2008). EXAMPLE 3 IN VIVO VALIDATION OF PEPTIDE ANALOGUES [00443] Hepcidin analogues of the present invention were tested for in vivo activity, to determine their ability to decrease free Fe2+ in serum. [00444] A hepcidin analogue or vehicle control were administered to mice (n=3/group) at 1000 nmol / kg either intravenously or subcutaneously. Serum samples were taken from groups of mice administered with the hepcidin analog at 30 min, 1 h, 2 h, 4 h, 10 h, 24 h, 30 h, 36 h, and 48 h post-administration. Iron content in plasma/serum was measured using a colorimetric assay on the Cobas c 111 according to instructions from the manufacturer of the assay (assay: IRON2: ACN 661). [00445] In another experiment, various hepcidin analogues or vehicle control were administered to mice (n=3/group) at 1000 nmol / kg subcutaneously. Serum samples were taken from groups of mice administered with vehicle or hepcidin analog at 30 h and 36 h post- administration. Iron content in plasma/serum was measured using a colorimetric assay on the Cobas c 111 according to instructions from the manufacturer of the assay (assay: IRON2: ACN 661). [00446] These studies demonstrate that hepcidin analogues of the present invention reduce serum iron levels for at least 30 hours, thus demonstrating their increased serum stability. EXAMPLE 4 IN VITRO VALIDATION OF PEPTIDE ANALOGUES [00447] Based in part on the structure activity relationships (SAR) determined from the results of the experiments described herein, a variety of Hepcidin-like peptides of the present invention were synthesized using the method described in Example 1, and in vitro activity was tested as described in Example 2. Reference compounds included native Hepcidin, Mini- Hepcidin, R1-Mini-Hepcidin, Reference Compound 1 and Reference Compound 2. EC50 values of the peptides are shown in summary Tables 6A-C. EXAMPLE 5 PLASMA STABILITY [00448] Plasma stability experiments were undertaken to complement the in vivo results and assist in the design of potent, stable Ferroportin agonists. In order to predict the stability in rat and mouse plasma, ex vivo stability studies were initially performed in these matrices. [00449] Peptides of interest (20 µM) were incubated with pre-warmed plasma (BioreclamationIVT) at 37°C. Aliquots were taken at various time points up to 24 hours (e.g. 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile/methanol (1:1) and 0.1% formic acid, containing 1 µM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 17,000 g for 15 minutes. The supernatant were diluted 1:1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half-lives were calculated by fitting to a first-order exponential decay equation using GraphPad. EXAMPLE 6 REDUCTION OF SERUM IRON IN MICE [00450] Hepcidin mimetic compounds, designed for oral stability, were tested for systemic absorption by PO dosing in a wild type mouse model C57BL/6. The animals were acclimatized in normal rodent diet for 4-5 days prior to study start and fasted overnight prior to study start. Groups of 4 animals each received either Vehicle or the Compounds. The compounds were formulated in Saline at a concentration of 5 mg/mL. The mice received dosing solution via oral gavage at volume of 200 µl per animal of body weight 20 g. Each group received 1 dose of compounds at 50 mg/kg/dose The group marked for vehicle received only the formulation. Blood was drawn at 4 hours post- dose and serum was prepared for PK and PD measurements. The compound concentration was measured by mass spectrometry method and iron concentration in the samples was measured using the colorimetric method on Roche cobas c system. EXAMPLE 7 REDUCTION OF SERUM IRON IN MICE [00451] In another experiment, a new set of compounds were tested for systemic absorption by PO dosing in a wild type mouse model C57BL/6. The animals were acclimatized in normal rodent diet for 4-5 days prior to study start. Over the night prior to the first dose, the mice were switched to a low iron diet (with 2ppm iron) and this diet was maintained during the rest of the study. Groups of 5 animals each received either Vehicle or the Compounds. The concentration of compounds was at 30 mg/mL, formulated in 0.7% NaCl + 10mM NaAcetate buffer. Food was withdrawn around 2 hours prior to each dose to ensure that the stomach was clear of any food particles prior to PO dosing. The mice received dosing solution via oral gavage at volume of 200 µl per animal of body weight 20 g. Each group received 2 doses of compound at 300 mg/kg/dose, on successive days. The group marked for vehicle received only the formulation. Blood was drawn at 4.5 hours post-last-dose and serum was prepared for PD measurements. Serum iron concentration was measured using the colorimetric method on Roche cobas c system. EXAMPLE 8 PHARMACODYNAMIC EFFECTS FOR THE SERUM IRON REDUCING ABILITIES OF A REPRESENTATIVE COMPOUND IN MICE [00452] In a second in vivo study, the representative compound was tested for pharmacodynamic effect with a single dose of 300 mg/kg/dose vs.2 doses of 300mg/kg over two days QD (once per day). C57BL/6 mice were acclimatized in normal rodent diet for 4-5 days prior to study start. Over the night prior to the first dose, the mice were switched to a low iron diet (with 2ppm iron) and this diet was maintained during the rest of the study. Groups of 5 animals each received either Vehicle or the Compounds. The compound was formulated in 0.7% NaCl + 10mM NaAcetate buffer at 30mg/mL concentration. Food was withdrawn around 2 hours prior to each dose to ensure that the stomach was clear of any food particles prior to PO dosing. The mice received dosing solution via oral gavage at volume of 200 µl per animal of body weight 20 g. EXAMPLE 9 PK/PD EFFECTS OF ORAL DOSING OF A REPRESENTATIVE COMPOUND OF THE PRESENT INVENTION IN MICE [00453] In another in vivo study with healthy Wild Type mouse model C57/BL6, representative Compound was tested for PK and PD effect with multiple dosing over three days. The mice were maintained under normal rodent feed during the acclimatization and switched to iron-deficient diet (with ~2ppm iron) one night prior to the first dose. Groups of 5 mice each received a total of 6 doses of either vehicle or a representative compound of the present invention at different dose strengths, in a BID format over three days. Mice were dosed via. oral gavage with the representative compound formulated in 0.7% saline and 10 mM Sodium Acetate. The different groups received either vehicle, 150 mg/kg/dose BID, 75 mg/kg/dose BID, 37.5 mg/kg/dose BID, or 18.75 mg/kg/dose BID. An additional group received 100 mg/kg/dose BID in addition to a total of 100 mg/kg/day of compound in drinking water (DW), thereby receiving a total dose of 300 g/kg/day. At 3 hours post-last-dose the vehicle group marked for iron-challenge and all the compound dosed groups received iron solution via. oral gavage at 4 mg/kg iron per animal. Blood was collected at 90 min post-iron- challenge to prepare serum for PK and PD measurements. The compound concentration was measured by mass spectrometry method and iron concentration in the samples was measured using the colorimetric method on Roche cobas c system. EXAMPLE 10 REDUCTION OF SERUM IRON IN MICE [0100] In a separate triage, a new set of compounds were tested for their pharmacodynamic effect when dosed orally in the wild type mouse model C57BL/6. The animals were acclimatized in normal rodent diet for 4-5 days prior to study start. The group of 5 animals designated to receive two doses of a representative compound received an iron-deficient diet (with 2-ppm iron) on the night prior to the first dose and all the other groups designated for single dose of different compounds were treated with iron-deficient diet for two nights prior to the compound dosing. The concentration of compounds in the dosing solution was at 30mg/mL, formulated in 07% NaCl + 10mM NaAcetate buffer Food was withdrawn around 2hours prior to any dosing to ensure that the stomach was clear of any food particles prior to PO dosing. The mice received dosing solution via oral gavage at volume of 200µl per animal of body weight 20g. The group marked for vehicle received only the formulation. Blood was drawn at 4.5hours post-last-dose and serum was prepared for PD measurements. Serum iron concentration was measured using the colorimetric method on Roche cobas c system. EXAMPLE 11 STABILITY IN SIMULATED GASTRIC FLUID [00454] Blank SGF was prepared by adding 2 g sodium chloride, 7 mL hydrochloric acid (37%) in a final volume of 1 L water, and adjusted pH to 1.2. [00455] SGF was prepared by dissolving 320 mg Pepsin (Sigma®, P6887, from Porcine Stomach Mucosa) in 100 mL Blank SGF and stirred at room temperature for 30 minutes. The solution was filtered through 0.45 µm membrane and aliquot and stored at -20 °C. [00456] Experimental compounds of interest (at a concentration of 20 µM) were incubated with pre-warmed SGF at 37°C. Aliquots were taken at various time points up to 24 hours (e.g., 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile/methanol (1:1) and 0.1% formic acid, containing 1 µM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 4,000 rpm for 10 minutes. The supernatant were diluted 1:1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half-lives were calculated by fitting to a first-order exponential decay equation using GraphPad. EXAMPLE 12 STABILITY IN SIMULATED INTESTINAL FLUIDS [00457] Blank FaSSIF was prepared by dissolving 0.348 g NaOH, 3.954 g sodium phosphate monobasic monohydrate and 6.186 g NaCl in a final volume of 1 liter water (pH adjusted to 6.5). [00458] FaSSIF was prepared by dissolving 1.2 g porcine pancreatin (Chem-supply, PL378) in 100 mL Blank FaSSIF and stirred at room temperature for 30 minutes. The solution was filtered through 0.45 µm membrane and aliquot and stored at -20 °C. [00459] Experimental compounds of interest (20 µM) were incubated with pre-warmed FaSSIF (1% pancreatin in final incubation mixture) at 37°C Aliquots were taken at various time points up to 24 hours (e.g.0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile/methanol (1:1) and 0.1% formic acid, containing 1 µM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 4,000 rpm for 10 minutes. The supernatant were diluted 1:1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half- lives were calculated by fitting to a first-order exponential decay equation using GraphPad. EXAMPLE 13 MODIFIED EXPERIMENTAL FOR PEPTIDES PRONE TO “NON-SPECIFIC BINDING” [00460] Compounds of interest (at concentration of 20 µM) were mixed with pre- warmed FaSSIF (1% pancreatin in final working solution). The solution mixture was aliquoted and incubated at 37°C. The number of aliquots required was equivalent to the number of time points (e.g. 0, 0.25, 1, 3, 6 and 24 hr). At each time point, one aliquot was taken and immediately quenched with 4 volumes of organic solvent (acetonitrile/methanol (1:1) and 0.1% formic acid, containing 1 µM internal standard). The remaining steps were the same as the generic experimental. [00461] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. [00462] At least some of the chemical names and sequences of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. In the instance where the indicated chemical name or sequence and the depicted structure differ, the depicted structure will control. In the chemical structures where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure. Similarly, for the peptides where E/Z isomers exists but are not specifically mentioned, both isomers are specifically disclosed and covered. [00463] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.