Conjugated hepcidin mimetic

Abstract

To provide compounds that possess hepcidin activity and also have other beneficial physical properties such as improved solubility, stability, and / or potency, so that they may be used to treat hepcidin-related diseases and disorders. [Solution] The present invention discloses hepcidin analogs having an improved in vivo half-life, related pharmaceutical compositions, and methods for using them.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is, This is a national phase application under Section 371 of the United States Patent Act, filed on July 28, 2021, with international application number PCT / US2021 / 043581. U.S. Provisional Patent Application No. 63 / 057,582, filed on July 28, 2020; U.S. Provisional Patent Application No. 63 / 057,577, filed on July 28, 2020; and U.S. Provisional Patent Application No. 63 / 169,527, filed on April 1, 2021; U.S. Provisional Patent Application No. 63 / 169,533, filed on April 1, 2021; U.S. Provisional Patent Application No. 63 / 169,515, filed on April 1, 2021; and U.S. Provisional Patent Application No. 63 / 057,583, filed on July 28, 2020; Under Section 119(e) of the United States Patent Act Claiming priority rights, each of these disclosures is incorporated herein by reference in its entirety.

[0002] Sequence List The contents of the electronic sequence listing (T094770000US07-SUBSEQ-EMB.txt, size: 285,400 bytes, creation date: December 3, 2025) are as follows: The entirety of it is incorporated herein by reference. 。

[0003] Field of Invention The present invention relates, in particular, to specific hepcidin peptide analogs, including both peptide monomers and peptide dimers, as well as their conjugates and derivatives, and compositions comprising peptide analogs, and to the use of peptide analogs in the treatment and / or prevention of various diseases, conditions, or disorders, including polycythemia such as polycythemia euna, iron overload diseases such as hereditary hemochromatosis, iron-loaded anemia, and other conditions and disorders described herein. [Background technology]

[0004] Background of the Invention Hepcidin (also known as LEAP-1), a peptide hormone produced by the liver, is a regulator of iron homeostasis in humans and other mammals. Hepcidin acts by binding to its receptor, the iron efferent channel ferroportin, causing its internalization and degradation. Human hepcidin is a 25-amino acid peptide (Hep25). See Krause et al. (2000) FEBS Lett 480:147-150 (Non-Patent Literature 1) and Park et al. (2001) J. Biol. Chem. 276:7806-7810 (Non-Patent Literature 2). The structure of the bioactive 25-amino acid form of hepcidin is a simple hairpin with eight cysteine ​​groups forming four disulfide bonds, as described in Jordan et al. J Biol Chem 284:24155-67 (Non-Patent Literature 3). The N-terminal region is essential for iron regulation, and the deletion of five N-terminal amino acid residues results in the loss of iron regulation function. See Nemeth et al. (2006) Blood 107:328-33 (Non-Patent Literature 4).

[0005] Abnormal hepcidin activity is associated with iron overload disorders, including hereditary hemochromatosis (HH) and iron-loading anemia. Hereditary hemochromatosis is a hereditary iron overload disorder caused primarily by hepcidin deficiency or, in some cases, hepcidin resistance. This can lead to excessive absorption of iron from the diet and the development of iron overload. Clinical manifestations of HH may include liver disease (e.g., cirrhosis, NASH, and hepatocellular carcinoma), diabetes, and heart failure. Currently, the only treatment for HH is regular phlebotomy, which is very burdensome for patients. Iron-loading anemia is a hereditary anemia accompanied by severe iron overload and ineffective red blood cell formation, such as β-thalassemia. Complications due to iron overload are the main cause of morbidity and mortality in these patients. Hepcidin deficiency is the main cause of iron overload in non-transfusion patients and a cause of iron overload in transfusion patients. The current treatment for iron overload in these patients is iron chelation, which is very burdensome, sometimes ineffective, and frequently accompanied by side effects.

[0006] Hepcidin involves a difficult synthesis process, partly due to protein aggregation and precipitation during folding, which subsequently has several limitations that restrict its use as a drug, resulting in low bioavailability, injection site reactions, immunogenicity, and high commercial costs. What is needed in the art is a hepcidin-like compound that possesses hepcidin activity and also has other beneficial physical properties such as improved solubility, stability, and / or potency, so that it can be readily manufactured and used to treat hepcidin-related diseases and disorders, such as those described herein.

[0007] To address this need, the present invention provides novel peptide analogs, including both peptide monomer analogs and peptide dimer analogs, that possess hepcidin activity and other beneficial properties that make the peptides of the present invention suitable substitutes for hepcidin. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Krause et al. (2000) FEBS Lett 480:147-150 [Non-Patent Document 2] Park et al. (2001) J.Biol.Chem.276:7806-7810 [Non-Patent Document 3] Jordan et al. J Biol Chem 284:24155-67 [Non-Patent Document 4] Nemeth et al.(2006)Blood 107:328-33 [Overview of the project]

[0009] The present invention generally relates to peptide analogs, including both monomers and dimers exhibiting hepcidin activity, and methods for using them.

[0010] In one embodiment, the present invention relates to formula (I): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula I, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp; Each Xaa1 and Xaa2 is independently Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N-substituted Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is an aminohexanoic acid moiety and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m where Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100K; Z is a half-life extension moiety; J is Lys, D-Lys, Arg, Pro, Pro-Arg-, Pro-Lys-, Pro-(D)Lys-, Pro-Arg-Ser-, Pro-Arg-Ser-Lys-(SEQ ID NO 136 ), -Pro-Arg-Ser-Lys-Sar (SEQ ID NO 250), -Pro-Arg-Ser-Lys-Gly (SEQ ID NO 251), His-(D)Phe-Arg-Trp (Sequence ID 137) or is absent, or J is any amino acid; Y1 is Cys, homoCys, (D)Cys, NMeCys, aMeCys, or Pen; Y2 is an amino acid or is absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I optionally contains one or more R 1PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0011] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0012] In one embodiment, Xaa1 is B5, where B5 is non-existent, Lys, or D-Lys, and Xaa2 is B7(L1Z), where B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0013] In another embodiment, Xaa1 is B5(L1Z), where B5 is Lys or D-Lys, and Xaa2 is B7, where B7 is Glu or absent.

[0014] In one embodiment, Xaa1 is Lys(Ac) and Xaa2 is (D)Lys(Ac).

[0015] In another embodiment, the present invention relates to formula (AI): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (AI) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula I, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (I); B7 is either Lys or D-Lys; Here: i) The peptide of formula I optionally contains one or more R 1PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 does not exist; iv) If the peptide is a peptide dimer, the peptide dimer is a) Through the linker portion, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes the half-life extension portion.

[0016] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0017] In another embodiment, the present invention relates to formula (BI): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (BI) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula BI, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (I); Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, Pro-Arg, Pro-Lys, Pro-(D)Lys, Pro-Arg-Ser, Pro-Arg-Ser-Lys (sequence number) 136 ) is either true or does not exist.

[0018] In one embodiment, the present invention relates to formula (I'): R 1 -Xbb1-Thr-X3-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I') A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Asp, isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, bGlu, Gla, or Glp; X3 is His or substitute His; Each Xaa1 and Xaa2 is independently Ala, Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, a-Me-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and 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 from 1 to 100K; Z is the half-life extension portion; J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, where each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly; Y1 is Abu, Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R 1PEGylated in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; However, if Xbb1 is Asp, R 1 C2~C 20 It is Alkenoil.

[0019] In one embodiment, the present invention relates to formula (XXI): R 1 -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (XXI) It contains a hepcidin analog containing the peptide, During the ceremony: L1, Z, J, Y1, and Y2 are as described for equation (I); R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal. B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is either Glu or does not exist.

[0020] In one aspect, the present invention relates to a peptide of formula (XXII): R 1 -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7(L1Z)-J-Y1-Y2-R 2 (XXII) and includes a hepcidin analog containing the peptide, wherein: L1, Z, J, Y1, and Y2 are as described for formula (I); R 1 is hydrogen, C1-C6 alkyl, C6-C 12 aryl, C6-C 12 aryl-C1-C6 alkyl, C1-C 20 alkanoyl, C2-C 20 alkenoyl, or C1-C 20 cycloalkanoyl; R 2 is NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or glnGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is Lys or (D)Lys.

[0021] In certain embodiments, -L1Z is -PEG11_OMe,​​​​​​​​​​​​​-PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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_Dioxide, -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18_diacid, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000340.tif19128. Ahx is -[C(O)-(CH2)5-NH]-, Cn diacid is -C(O)-(CH2) n-2 It is -COOH, and n is 10, 12, 14, 16, 18, or 22.

[0022] In certain embodiments of the hepcidin analogs disclosed herein, the half-life extension portion is C 10 ~C21 is alkanoyl.

[0023] In a particular embodiment, B7 is Lys, D-Lys, homo-Lys, or a-Me-Lys.

[0024] In certain embodiments of either the hepcidin analog or dimer of the invention, the linker moiety is selected from iso-Glu, Dapa, PEGn (n = 1-25), PEG11 (40 atoms), OEG, iso-Glu-Ahx, iso-Glu-OEG-OEG, iso-Glu-PEG5, iso-Glu-PEGn, PEGn-iso-Glu, PEGn-Ahx (n = 1-25), βAla-PEG2), and βAla-PEG11 (40 atoms). In certain embodiments, two or more linker moieties are conjugated to the peptide of the hepcidin analog or dimer.

[0025] In one embodiment, B5 is Lys. In another embodiment, B7 is Lys.

[0026] In one embodiment, B5 is D-Lys. In another embodiment, B7 is D-Lys.

[0027] In one aspect, the invention provides a peptide of formula (LI): R 1 -Xbb1-Xcc1-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LI) a hepcidin analog comprising the peptide, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is hydrogen, C1-C6 alkyl, C6-C 12 aryl, C6-C 12 aryl-C1-C6 alkyl, C1-C 20 alkanoyl, or C1-C 20 cycloalkanoyl; R 2 is NH2 or OH; Xbb1 is isoAsp, Asp(OMe), Glu, bhGlu, bGlu, Gla, or Glp; Either Xcc1 is any amino acid other than Thr and Xdd1 is any amino acid, or Xcc1 is any amino acid and Xdd1 is any amino acid other than His. Xaa1 is B5, i) Whether B5 is nonexistent, Lys, D-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, Or, ii) Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is the aminohexanoic acid moiety and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence number 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or none of the above, or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen, and Y2 is an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0028] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0029] In one embodiment, Xaa1 is B5, where B5 is non-existent, Lys, or D-Lys, and Xaa2 is B7(L1Z), where B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0030] In another embodiment, Xaa1 is B5(L1Z), where B5 is Lys or D-Lys, and Xaa2 is B7, where B7 is Glu or absent.

[0031] In another embodiment, the present invention relates to formula (LI-AI) or (LI-A2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A1), or R 1 -Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A2) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, Where: Xbb1, Xcc1, Xdd1, R 1 , R 2 , B1 to B6, L1, Z, J, Y1, and Y2 are as described for formula (LI); B7 is Lys or D-Lys; Here: i) The peptide of formula I is optionally PEGylated at one or more of R 1 , B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) When the peptide is a peptide dimer, B7(L1Z)-J-Y1-Y2 does not exist; iv) When the peptide is a peptide dimer, the peptide dimer is a) via a linker moiety, b) in one of each monomer subunit, via an intermolecular disulfide bond between two B3 residues, or c) via both a linker moiety and an intermolecular disulfide bond between two B3 residues, dimerized, d) The linker moiety contains a half-life extension moiety.

[0032] In one embodiment, the half-life extension moiety is C 10 ~C 21 alkanoyl.

[0033] In another aspect, the present invention provides a compound of formula (LI-B1) or (LI-B2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LI-B1), or R 1 -Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R2 (LI-B2) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (LI); Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg, -Pro-Lys, -Pro-(D)Lys, -Pro-Arg-Ser, -Pro-Arg-Ser-Lys-(Array No. 136 ) is either true or does not exist.

[0034] In certain embodiments of the hepcidin analogs disclosed herein, the half-life extension portion is C 10 -C 21 It is Alkanoyl.

[0035] In one particular embodiment, B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0036] In certain embodiments of the hepcidin analog or dimer of the present invention, the linker moiety is selected from isoGlu, Dapa, PEGn (n=1-25), PEG11 (40 atoms), OEG, isoGlu-Ahx, isoGlu-OEG-OEG, isoGlu-PEG5, isoGlu-PEGn, PEGn-isoGlu, PEGn-Ahx (n=1-25), βAla-PEG2, and βAla-PEG11 (40 atoms). In certain embodiments, two or more linker moieties are conjugated to the hepcidin analog or dimer peptide.

[0037] In one embodiment, B5 is Lys. In another embodiment, B7 is Lys.

[0038] In one embodiment, B5 is D-Lys. In another embodiment, B7 is D-Lys.

[0039] In certain embodiments of the hepcidin analog or dimer of the present invention, the half-life extension portion is selected from C12 (lauric acid), C14 (myristic acid), C16 (palmitic acid), C18 (stearic acid), C20, C12 diacitate, C14 diacitate, C16 diacitate, C18 diacitate, C20 diacitate, biotin, and isovaleric acid, or residues thereof. In certain embodiments, the half-life extension portion is bound to a linker portion that is attached to the peptide. In certain embodiments, the half-life extension portion increases the molecular weight of the hepcidin analog by about 50 D to about 2 KD. In various embodiments, the half-life extension portion increases the serum half-life of the hepcidin analog, improves solubility, and / or improves bioavailability.

[0040] In certain embodiments, the peptide analog or dimer of the present invention comprises an isovaleric acid moiety conjugated to the N-terminal Asp residue.

[0041] In certain embodiments, the peptide analog of the present invention comprises an amidated C-terminal residue.

[0042] In certain embodiments, the present invention provides a hepcidin analog comprising any hepcidin analog or peptide disclosed herein, or comprising or comprising any sequence or structure disclosed herein, the hepcidin analog or peptide comprising, but not limited to, a disulfide bond between two Cys residues.

[0043] In certain embodiments, the hepcidin analog or dimer of the present invention includes Asp-Thr-His-Phe-Pro-Cys-Ile-Lys-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys (SEQ ID NO: 252), or a sequence having at least 80%, at least 90%, or at least 94% identity with this sequence.

[0044] In certain embodiments, the hepcidin analog or dimer of the present invention is Asp-Thr-His-Phe-Pro-Cys-Ile-Lys-Phe-Lys-Pro-Arg-Ser-Lys-Gly-Cys-Lys(SEQ ID NO: 139 ), or a sequence having at least 80%, at least 90%, or at least 94% identity with this sequence.

[0045] In related embodiments, the present invention includes polynucleotides encoding peptides of the hepcidin analog or dimer (or monomeric subunit of the dimer) of the present invention.

[0046] In further related embodiments, the present invention includes a vector comprising the polynucleotide of the present invention. In certain embodiments, the vector is an expression vector comprising, for example, a promoter operably linked to the polynucleotide by means of promoting the expression of the polynucleotide.

[0047] In another embodiment, the present invention includes a pharmaceutical composition comprising a hepcidin analog, dimer, polynucleotide, or vector of the present invention and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0048] In another embodiment, the present invention provides a method for conjugating ferroportin or for inducing ferroportin internalization and degradation, comprising contacting ferroportin with at least one hepcidin analog, dimer, or composition of the present invention.

[0049] In further embodiments, the present invention includes a method for treating a disease of iron metabolism in a subject that needs it, and includes providing the subject with an effective amount of the pharmaceutical composition of the present invention. In certain embodiments, the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, spray, sublingual, buccal, parenteral, rectal, vaginal, or topical route of administration. In certain embodiments, the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration. In certain embodiments, the disease of iron metabolism is a disease of iron overload. In certain embodiments, the pharmaceutical composition is provided to the subject at a maximum or about twice a day, at a maximum or about once a day, at a maximum or about once every two days, at a maximum or about once a week, or at a maximum or about once a month.

[0050] In certain embodiments, the hepcidin analog is provided to the subject in doses of approximately 1 mg to approximately 100 mg or approximately 1 mg to approximately 5 mg.

[0051] In another embodiment, the present invention provides a device comprising the pharmaceutical composition of the present invention for optionally oral or subcutaneous delivery of a hepcidin analog or dimer of the present invention.

[0052] In yet another embodiment, the present invention includes a kit comprising a pharmaceutical composition of the present invention, packaged together with a reagent, a device, or instructions, or a combination thereof. [Invention 1001] Equation I': R 1 -Xbb1-Thr-X3-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I') A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Asp, isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, bGlu, Gla, or Glp; X3 is His or substitute His; Each Xaa1 and Xaa2 is independently Ala, Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, a-Me-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and 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 from 1 to 100K; Z is the half-life extension portion; J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, where each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly; Y1 is Abu, Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R 1 PEGylated in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; However, if Xbb1 is Asp, R 1 However, C2~C 20 It is Alkenoil. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1002] Xbb1 is Asp, R 1 However, C2~C 20 A hepcidin analog containing the peptide of the present invention 1001, which is an alkenoyl. [Invention 1003] A hepcidin analog comprising the peptide of Invention 1001, wherein Xbb1 is (D)Glu or (D)IsoGlu. [Invention 1004] A hepcidin analog comprising the peptide of Invention 1001, wherein Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp. [Invention 1005] A hepcidin analog containing the peptide of the present invention 1001, wherein B1 is Dpa. [Invention 1006] A hepcidin analog comprising the peptide of Invention 1001, wherein Xaa1 is B5(L1Z), B5 is Lys, D-Lys, Dap, or Dap-Dap, and Xaa2 is B7, where B7 is Glu or absent. [Invention 1007] A hepcidin analog comprising the peptide of the present invention 1001, which is Pro or NPC. [Invention 1008] A hepcidin analog comprising the peptide of the present invention 1001, wherein X7 is Ile. [Invention 1009] A hepcidin analog comprising the peptide of the present invention 1001, wherein B9 is Phe or bhPhe. [Invention 1010] A hepcidin analog comprising the peptide of Invention 1001, wherein J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, and each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly. [Invention 1011] J is Arg, Lys, D-Lys, Spiro_pip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -Pro-Lys(Ac)-, -Pro-(D)Lys(Ac)-, -Pro-Arg-Ser-Lys(Ac)-(SEQ ID NO: 249), -Pro-Arg-Ser-Lys(Ac)-Sar-(SEQ ID NO: 250), -Pro-Arg- A hepcidin analog comprising the peptide of Invention 1001, wherein Ser-Lys(Ac)-Gly-, -hydroxyPro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -Pro-MeArg-Ser-Lys-Gly-, -Pro-Arg-MeSer-Lys-Gly-(SEQ ID NO: 251), (SEQ ID NO: 251), -Pro-Lys(Ac)-Ser-Lys(Ac)-, -Pro-Lys(Ac)-Ser-Lys(Ac)-Gly-, -Pro-Lys(Ac)-Ser-Lys(Ac)-Gly-, -Pro-Lys(Ac)-Ser-Lys(Ac)-Sar-, -Pro-Arg-Ser-MeLys-Gly or absent, or J is any amino acid. [Invention 1012] A hepcidin analog comprising the peptide of Invention 1001, wherein J is Arg, Lys, D-Lys, Spiropip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or J is any amino acid. [Invention 1013] Formula I: R 1-Xbb1-Thr-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I) A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp; Each Xaa1 and Xaa2 is independently Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is either Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -His-(D)Phe-Arg-Trp-Cys-, or is absent, or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R 1 PEGylated in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1014] A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof, wherein each Xaa1 and Xaa2 is independently Lys, Lys(Ac), (D)Lys, or (D)Lys(Ac). [Invention 1015] A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is Lys(Ac) and Xaa2 is (D)Lys(Ac). [Invention 1016] A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5, and B5 is absent, Lys, or D-Lys, and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys. [Invention 1017] A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5(L1Z), B5 is Lys or D-Lys, Xaa2 is B7, and B7 is Glu or absent. [Invention 1018] The aforementioned peptide is given by formula AI: R 1 -Xbb1-Thr-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (AI) This is due to, During the ceremony: R 1 , R 2 , B1~B6, L1, Z, J, Y1, and Y2 are as per the present invention 1001; B7 is either Lys or D-Lys; Here: i) The peptide optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, then B5 is not Lys. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1019] The aforementioned peptide is given by formula BI: R1 -Xbb1-Thr-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (BI) This is due to, During the ceremony: R 1 , R 2 , B1~B6, L1, Z, J, Y1, and Y2 are as per the present invention 1001; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (sequence number 249) or does not exist. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1020] A hepcidin analog of any of the present invention 1001 to 1007, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is F, Dpa, BIP, or bhPhe, B2 is Pro, NCP, (D)Pro, or (D)NCP, B3 is Cys, α-MeCys, or homoCys, B4 is Ile, B5 is Lys, or (D)Lys, B6 is Phe, substituted Phe, bhPhe, or 2Pal, and B7 is Lys, or (D)Lys. [Invention 1021] A hepcidin analog of any of Invention 1001 to 1007, or a pharmaceutically acceptable salt or solvate thereof, wherein B2 is Pro or NPC, B3 is Cys, B4 is Ile, and B6 is Phe, bhPhe, or 2Pal. [Invention 1022] B7(L1Z) is -N(H)C[CH2(CH2CH2CH2) m A hepcidin analog of any of the inventions 1004 to 1009, which is N(H)L1Z](H)-C(O)- and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1023] A hepcidin analog of any of the inventions 1004 to 1009, wherein B7(L1Z) is -N(H)C[CH2N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1024] A hepcidin analog of any of the inventions 1004 to 1009, wherein B7(L1Z) is -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1025] The peptide is of formula IV or V: R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (IV), or R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (V) This is due to, During the ceremony: R 1 , R 2 , L1, Z, J, Y1, and Y2 are as described in Invention 1001; B1 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), B5 is (D)Lys, and B6 is Phe, bhPhe, 2Pal. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1026] A hepcidin analog of the present invention 1013, or a pharmaceutically acceptable salt or solvate thereof, wherein B5 is (D)Lys. [Invention 1027] The peptide is of formula VI or CIIb: R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (VI), or R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (VII) This is due to, During the ceremony: R 1 , R 2 , L1, Z, J, Y1, and Y2 are as described in Invention 1001; B1 is Phe, Phe(4-F), Phe(4-CF3), or Phe(2,3,5-trifluoro), and B6 is Phe, bhPhe, or 2Pal. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1028] A hepcidin analog according to any of the invention items 1013 to 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Phe, Phe(4-F), Phe(4-CF3), or Phe(2,3,5-trifluoro). [Invention 1029] A hepcidin analog according to any of invention 1013 to 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa. [Invention 1030] The peptide is of formula VIII or IX: R 1 -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R2 (VIII), or R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (IX) This is due to, During the ceremony: R 1 , R 2 , L1, Z, J, Y1, and Y2 are as described in Invention 1001; B6 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), bhPhe, 2Pal. A hepcidin analog of the present invention 1004, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1031] A hepcidin analog of any of the inventions 1001 to 1018, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is Phe. [Invention 1032] A hepcidin analog of any of the present invention 1001 to 1018, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe. [Invention 1033] The peptide is of formula Xa, Xb, Xc, or Xd: R 1 -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xa) R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xb) R 1-Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xc) R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xd) This is due to, During the ceremony: R 1 , R 2 L1, Z, J, Y1, and Y2 are as described in Invention 1001. A hepcidin analog of any of invention 1013 to 1020, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1034] A hepcidin analog of any of the invention items 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys-(SEQ ID NO: 253), -Pro-Arg-Ser-Lys-Cys-(SEQ ID NO: 254), -His-(D)Phe-Arg-Trp-Cys-, or -Pro-Arg-Ser-Lys-Sar-Cys-(SEQ ID NO: 255). [Invention 1035] A hepcidin analog of any of the inventions 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-. [Invention 1036] A hepcidin analog of any of the inventions 1001 to 1021, wherein -J-Y1-Y2- is -Cys-(D)Lys-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1037] A hepcidin analog of any of the inventions 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys- (SEQ ID NO: 254). [Invention 1038] A hepcidin analog of any of the inventions 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-Lys- (SEQ ID NO: 255). [Invention 1039] A hepcidin analog of any of the inventions 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Pro-Cys-. [Invention 1040] A hepcidin analog of any of the inventions 1001 to 1021, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Cys-. [Invention 1041] A hepcidin analog of any of the inventions 1001 to 1021, wherein -J-Y1-Y2- is -(D)Lys-Pen-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1042] A hepcidin analog of any of the invention items 1001 to 1029, in which L1 is a single bond, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1043] A hepcidin analog according to any of the invention items 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu. [Invention 1044] A hepcidin analog according to any of the invention items 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is Ahx. [Invention 1045] A hepcidin analog according to any of the invention items 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-Ahx. [Invention 1046] L1 is PEG, and is a hepcidin analog of any of invention 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1047] A hepcidin analog according to any of the inventions 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG-Ahx. [Invention 1048] A hepcidin analog according to any of the inventions 1001 to 1029, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-PEG-Ahx. [Invention 1049] A hepcidin analog of any of the present inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein PEG is -[C(O)-CH2-(Peg)nN(H)]m- or -[C(O)-CH2-CH2-(Peg)nN(H)]m-, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100, or 10K, 20K, or 30K. [Invention 1050] A hepcidin analog of any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. [Invention 1051] A hepcidin analog of any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. [Invention 1052] A hepcidin analog of any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. [Invention 1053] A hepcidin analog according to any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. [Invention 1054] A hepcidin analog according to any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 8. [Invention 1055] A hepcidin analog according to any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 11. [Invention 1056] A hepcidin analog according to any of the inventions 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 12. [Invention 1057] A hepcidin analog according to any of Invention 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 20K. [Invention 1058] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 1Peg2, and 1Peg2 is -C(O)-CH2-(Peg)2-N(H)-. [Invention 1059] A hepcidin analog according to any of Invention 1001 to 1036, wherein PEG is 2Peg2, and 2Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1060] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 1Peg2-1Peg2, and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1061] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1062] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 2Peg4, and 2Peg4 is -C(O)-CH2-CH2-(Peg)4-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1063] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 1Peg8, and 1Peg8 is -C(O)-CH2-(Peg)8-N(H)- or -[C(O)-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1064] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 2Peg8, and 2Peg8 is -C(O)-CH2-CH2-(Peg)8-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1065] A hepcidin analog according to any of the inventions 1001 to 1036, wherein PEG is 1Peg11, and 1Peg11 is -C(O)-CH2-(Peg)11-N(H)- or -[C(O)-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1066] A hepcidin analog according to any of Invention 1001 to 1036, wherein PEG is 2Peg11, and 2Peg11 is -C(O)-CH2-CH2-(Peg)11-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)11-NH]-. [Invention 1067] A hepcidin analog according to any of the inventions 1001 to 1036, 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]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1068] A hepcidin analog according to any of the present invention 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Lys, the -C(O)- of PEG is bound to the Ne of Lys. [Invention 1069] A hepcidin analog according to any of the inventions 1001 to 1036, wherein when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu. [Invention 1070] A hepcidin analog according to any of the Invention 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx. [Invention 1071] A hepcidin analog according to any of the Invention 1001 to 1036, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Palm, the -N(H)- of PEG is bound to the -C(O)- of Palm. [Invention 1072] A hepcidin analog of any of the inventions 1001 to 1059, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Palm. [Invention 1073] Z is a diacid, a hepcidin analog of any of the inventions 1001 to 1059, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1074] A hepcidin analog according to any of the inventions 1001 to 1059, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a C8-C20 diacid. [Invention 1075] A hepcidin analog according to any of the invention 1001 to 1059, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a C8-C20 diacid, one of the acid groups is bonded to L1, and the other acid group is free -C(O)2H. [Invention 1076] A hepcidin analog according to any of invention 1073 to 1075, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a C10, C12, C14, C16, or C18 diacid. [Invention 1077] The aforementioned peptide is given by formula XXI: R 1-Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (XXI) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as per the invention 1001; R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is either Glu or does not exist. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1078] -L1Z is, -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000341.tif19128. Ahx is -[C(O)-(CH2)5-NH]- A hepcidin analog according to any of invention 1001 to 1077, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1079] -L1Z is, -1PEG2_1PEG2_Dap_C18_Dioxide, -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18_diacid, During the ceremony: PEG2, PEG8, PEG4, and PEG12 are as described in Invention 1078, Cn diacid is -C(O)-(CH2) n-2-COOH, where n is 10, 12, 14, 16, 18, or 22. A hepcidin analog according to any of invention 1001 to 1077, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1080] The aforementioned peptide is given by formula XXII: R 1 -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7(L1Z)-J-Y1-Y2-R 2 (XXII) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as per the present invention; R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is Lys or (D)Lys. A hepcidin analog of the present invention 1001, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1081] -Each L1Z is independent, -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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_Dioxide -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18_diacid, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000342.tif19128. Ahx is -[C(O)-(CH2)5-NH]-, Cn diacid is -C(O)-(CH2) n-2-COOH, where n is 10, 12, 14, 16, 18, or 22. A hepcidin analog of the present invention 1080, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1082] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_isoGlu_C n It is a diacid, and Lys(1PEG2_1PEG2_isoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000343.tif21148, and n is 10, 12, 14, 16, or 18. [Invention 1083] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(1PEG2_1PEG2_isoGlu_C n (Diacid) and (D)Lys(1PEG2_1PEG2_isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000344.tif21148, and n is 10, 12, 14, 16, or 18. [Invention 1084] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG8_isoGlu_C n It is a diacid, and Lys(1PEG8_isoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000345.tif21148, and n is 10, 12, 14, 16, or 18. [Invention 1085] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(1PEG8_isoGlu_C n(Diacid) and (D)Lys(1PEG8_isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000346.tif21148, and n is 10, 12, 14, 16, or 18. [Invention 1086] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_Dap_C n _Diacid) and Lys(1PEG2_1PEG2_Dap_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000347.tif25138, and n is 10, 12, 14, 16, or 18. [Invention 1087] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(isoGlu_C n _Diacid) and Lys(isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein the formula is TIFF2026048851000348.tif21128, and n is 10, 12, 14, 16, or 18. [Invention 1088] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(IsoGlu_C n (Diacid) and (D)Lys(IsoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000349.tif21128, and n is 10, 12, 14, 16, or 18. [Invention 1089] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_isoGlu_C n It is a diacid, and Lys(PEG12 isoGlu C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000350.tif19128, and n is 10, 12, 14, 16, or 18. [Invention 1090] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_isoGlu_C n (Diacid) and (D)Lys(PEG12_isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000351.tif19128 and n is 10, 12, 14, 16, or 18. [Invention 1091] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_isoGlu_C n It is a diacid, and Lys(PEG4_isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000352.tif21137 and n is 10, 12, 14, 16, or 18. [Invention 1092] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_isoGlu_C n (Diacid) and (D)Lys(PEG4_isoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000353.tif21139, and n is 10, 12, 14, 16, or 18. [Invention 1093] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_PEG4_isoGlu_C n It is a diacid, and Lys(PEG4_PEG4_isoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000354.tif21137 and n is 10, 12, 14, 16, or 18. [Invention 1094] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_PEG4_isoGlu_C n (D)Lys(PEG4_PEG4_isoGlu_C) n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000355.tif21137, and n is 10, 12, 14, 16, or 18. [Invention 1095] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(isoGlu_C n _Diacid) and Lys(isoGlu_C n _Diacid) is, A hepcidin analog of any of the Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000356.tif24128 and n is 10, 12, 14, 16, or 18. [Invention 1096] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(IsoGlu_C n(Diacid) and (D)Lys(IsoGlu_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000357.tif24128 and n is 10, 12, 14, 16, or 18. [Invention 1097] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C n _Diacid) and Lys(PEG12_Ahx_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein TIFF2026048851000358.tif21130, and n is 10, 12, 14, 16, or 18. [Invention 1098] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C n _Diacid) and Lys(PEG12_Ahx_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein TIFF2026048851000359.tif21130, and n is 10, 12, 14, 16, or 18. [Invention 1099] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_Ahx_C n (Diacid) and (D)Lys(PEG12_Ahx_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein TIFF2026048851000360.tif21130, and n is 10, 12, 14, 16, or 18. [Invention 1100] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_C n _Diacid) and Lys(PEG12_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000361.tif21128, and n is 10, 12, 14, 16, or 18. [Invention 1101] Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_C n (Diacid) and (D)Lys(PEG12_C n _Diacid) is, A hepcidin analog of any of Invention 1001 to 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein n is TIFF2026048851000362.tif21128 and n is 10, 12, 14, 16, or 18. [Invention 1102] A hepcidin analog according to any of Invention 1001 to 1102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu, (Me)Glu, (OMe)Glu, hGlu, or bhGlu. [Invention 1103] A hepcidin analog according to any of Invention 1001 to 1102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is iso-Asp or Asp(OMe). [Invention 1104] A hepcidin analog according to any of Invention 1001 to 1102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Gla or Glp. [Invention 1105] Xbb1 is Glu, and is a hepcidin analog of any of invention 1001 to 1102, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1106] A hepcidin analog according to any of Invention 1001 to 1102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu, Glu-OMe, isoGlu, (D)Glu, or (D)isoGlu. [Invention 1107] A hepcidin analog according to any of the inventions 1001 to 1106, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa or Phe. [Invention 1108] A hepcidin analog according to any of the present inventions 1001 to 1106, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa. [Invention 1109] A hepcidin analog according to any of the inventions 1001 to 1108, or a pharmaceutically acceptable salt or solvate thereof, wherein B2 is Pro, Pro propanoate, Pro butanoate, bhPro, or NPC. [Invention 1110] B2 is Pro, and is a hepcidin analog of any of the inventions 1001 to 1108, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1111] A hepcidin analog of any of the present inventions 1001 to 1110, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe or Phe. [Invention 1112] A hepcidin analog of any of the present inventions 1001 to 1110, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe. [Invention 1113] A hepcidin analog of any of the inventions 1001 to 1112, or a pharmaceutically acceptable salt or solvate thereof, wherein B7 is Glu or absent. [Invention 1114] A hepcidin analog according to any of the inventions 1001 to 1112, or a pharmaceutically acceptable salt or solvate thereof, wherein B7 is Glu. [Invention 1115] A hepcidin analog of any of the inventions 1001 to 1112, or a pharmaceutically acceptable salt or solvate thereof, in which B7 is absent. [Invention 1116] A hepcidin analog of any of the inventions 1001 to 1115, or a pharmaceutically acceptable salt or solvate thereof, wherein J is (D)Lys, MeLys, or Arg. [Invention 1117] A hepcidin analog of any of Invention 1001 to 1115, or a pharmaceutically acceptable salt or solvate thereof, wherein J is (D)Lys. [Invention 1118] A hepcidin analog according to any of the inventions 1001 to 1117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is Cys, (D)Cys, NMeCys, aMeCys, or Pen. [Invention 1119] A hepcidin analog according to any of the present inventions 1001 to 1117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is Cys. [Invention 1120] R 2 However, the hepcidin analog of any of the invention items 1001 to 1019, which is NH2, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1121] R 2 However, the hepcidin analog of any of the inventions 1001 to 1019, or a pharmaceutically acceptable salt or solvate thereof, is an OH group. [Invention 1122] A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The peptide is one of the peptides listed in Tables 2A to 2B, and the peptide is cyclized via a disulfide bond between two Cys molecules. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1123] It is a peptide, The peptide in question contains or consists of one of the peptides listed in Tables 2A to 2B. The peptide is cyclized via a disulfide bond between two Cys molecules. *The peptide in which Peg11 is Peg11-OMe. [Invention 1124] A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The aforementioned peptide Compound ID number 12 TIFF2026048851000363.tif27151 Compound ID number 19 TIFF2026048851000364.tif118151 Compound ID number 107 TIFF2026048851000365.tif41151 Compound ID number 113 TIFF2026048851000366.tif22151 Compound ID number 256 TIFF2026048851000367.tif27151 Compound ID number 257 TIFF2026048851000368.tif27151 Compound ID number 280 TIFF2026048851000369.tif53151 Compound ID number 281 The hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, is TIFF2026048851000370.tif62151. [Invention 1125] A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The aforementioned peptide Compound ID number 255 TIFF2026048851000371.tif27151 or Compound ID280 The hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, is TIFF2026048851000372.tif53151. [Invention 1126] Formula LI: R 1 -Xbb1-Xcc1-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LI) Xc A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is isoAsp, Asp(OMe), Glu, bhGlu, bGlu, Gla, or Glp; Xcc1 is any amino acid other than Thr, and Xdd1 is any amino acid, or Xcc1 is any amino acid, and Xdd1 is any amino acid other than His; Xaa1 is B5, i) B5 is nonexistent, Lys, D-Lys, or Lys(Ac), Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or ii) Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, 2Pal, or Ala; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, D-NPC, Ala, MeAla, or Leu; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Ile, Val, Leu, or NLeu, Ala, or MeILe; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and 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 from 1 to 100K; Z is the half-life extension portion; J is either Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or is absent, or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I optionally contains one or more R 1PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1127] A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is any amino acid other than Thr and Xdd1 is any amino acid. [Invention 1128] A hepcidin analog of the present invention 1127, wherein Xdd1 is His. [Invention 1129] Formula LII: R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LII) Contains peptides produced by During the ceremony: Xcc1 is any amino acid other than Thr, and R 1 , R 2 Xaa1, Xbb1, B1~B4, B6, J, Y1, and Y2 are as described in Invention 1126. A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1130] A hepcidin analog of the present invention 1129, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is substituted with Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab. [Invention 1131] A hepcidin analog of the present invention 1129, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala. [Invention 1132] A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is any amino acid and Xdd1 is any amino acid other than His. [Invention 1133] A hepcidin analog of the present invention 1132, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is Thr. [Invention 1134] Formula LIII: R 1 -Xbb1-Thr-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LIII) Contains peptides produced by During the ceremony: Xdd1 is any amino acid other than His, and R 1 , R 2 Xaa1, Xbb1, B1~B4, B6, J, Y1, and Y2 are as described in Invention 1126. A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1135] A hepcidin analog of the present invention 1134, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substituted His. [Invention 1136] A hepcidin analog of the present invention 1134, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu. [Invention 1137] A hepcidin analog of any of the inventions 1126 to 1136, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5, and B5 is absent, Lys, or D-Lys, and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys. [Invention 1138] A hepcidin analog of any of Invention 1126 to 1136, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5(L1Z), B5 is Lys or D-Lys, Xaa2 is B7, and B7 is Glu or absent. [Invention 1139] Formula (LI-A1) or (LI-A2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A1), or R 1 -Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A2) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 , B1~B6, L1, Z, J, Y1, and Y2 are as per Invention 1126; B7 is either Lys or D-Lys; Here: i) The peptide optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, then B5 is not Lys; iv) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 is not present; v) If the peptide is a peptide dimer, the peptide dimer a) Through the linker portion, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes a half-life extension portion, A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1140] Formula (LI-B1) or (LI-B2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LI-B1), or R 1 -Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LI-B2) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 , B1~B6, L1, Z, J, Y1, and Y2 are as per Invention 1126; Here: i) The peptide optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (sequence number 249) or does not exist. A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1141] A hepcidin analog of any of the Invention 1126 to 1140, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is F, Dpa, BIP, or bhPhe, B2 is Pro, NCP, (D)Pro, or (D)NCP, B3 is Cys, α-MeCys, or homoCys, B4 is Ile, B5 is Lys, or (D)Lys, B6 is Phe, substituted Phe, bhPhe, or 2Pal, and B7 is Lys or (D)Lys. [Invention 1142] A hepcidin analog according to any of the present inventions 1126 to 1140, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa. [Invention 1143] B2 is Pro, and is a hepcidin analog of any of the inventions 1126 to 1142, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1144] A hepcidin analog according to any of the inventions 1126 to 1143, or a pharmaceutically acceptable salt or solvate thereof, wherein B3 is Cys. [Invention 1145] A hepcidin analog according to any of the present inventions 1126 to 1144, or a pharmaceutically acceptable salt or solvate thereof, wherein B4 is Ile. [Invention 1146] A hepcidin analog according to any of Invention 1126 to 1145, or a pharmaceutically acceptable salt or solvate thereof, wherein B5 is (D)Lys. [Invention 1147] A hepcidin analog according to any of the inventions 1126 to 1146, or a pharmaceutically acceptable salt or solvate thereof, wherein B5 is Lys(Ac). [Invention 1148] A hepcidin analog according to any of the present inventions 1126 to 1147, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe. [Invention 1149] B7(L1Z) is -N(H)C[CH2(CH2CH2CH2) mA hepcidin analog according to any of the inventions 1126 to 1148, wherein the compound is N(H)L1Z](H)-C(O)- and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1150] A hepcidin analog of any of the inventions 1126 to 1149, wherein B7(L1Z) is -N(H)C[CH2N(H)L1Z](H)-C(O)-. [Invention 1151] A hepcidin analog according to any of the inventions 1126 to 1149, wherein B7(L1Z) is -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1152] Formula LIV or LV: R 1 -Xbb1-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LIV), or R 1 -Xbb1-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LV) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described in Invention 1126. A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1153] A hepcidin analog according to any of Invention 1126 to 1152, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu, hGlu, or bhGlu. [Invention 1154] A hepcidin analog according to any of Invention 1126 to 1152, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is isoAsp or Asp(OMe). [Invention 1155] Xbb1 is Glu, and is a hepcidin analog of any of the inventions 1126 to 1152, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1156] Formula LVI or LVII: R 1 -Glu-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LVI), or R 1 -Glu-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LVII) Contains peptides produced by During the ceremony: Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described in Invention 1126. A hepcidin analog of the present invention 1126, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1157] A hepcidin analog of any of the Invention 1126 to 1156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is substituted with Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab. [Invention 1158] A hepcidin analog of any of Invention 1126 to 1156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala. [Invention 1159] A hepcidin analog according to any of Invention 1126 to 1156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is Ser, (D)Ser, or Ala. [Invention 1160] A hepcidin analog of any of Invention 1126 to 1156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substituted His. [Invention 1161] A hepcidin analog of any of Invention 1126 to 1156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu. [Invention 1162] A hepcidin analog of any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys-(SEQ ID NO: 253), -Pro-Arg-Ser-Lys-Cys-(SEQ ID NO: 254), or -Pro-Arg-Ser-Lys-Sar-Cys-(SEQ ID NO: 255). [Invention 1163] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-. [Invention 1164] A hepcidin analog according to any of the inventions 1126 to 1161, wherein -J-Y1-Y2- is -(D)Lys-Cys, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1165] A hepcidin analog according to any of the inventions 1126 to 1161, wherein -J-Y1-Y2- is -Arg-Cys, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1166] A hepcidin analog of any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a single bond. [Invention 1167] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu. [Invention 1168] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is Ahx. [Invention 1169] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-Ahx. [Invention 1170] L1 is PEG, and is a hepcidin analog of any of invention 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1171] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG-Ahx. [Invention 1172] A hepcidin analog according to any of the inventions 1126 to 1161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-PEG-Ahx. [Invention 1173] A hepcidin analog according to any of Invention 1126 to 1172, or a pharmaceutically acceptable salt or solvate thereof, wherein PEG is -[C(O)-CH2-(Peg)nN(H)]m- or -[C(O)-CH2-CH2-(Peg)nN(H)]m-, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100, or 10K, 20K, or 30K. [Invention 1174] A hepcidin analog according to any of the inventions 1126 to 1173, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. [Invention 1175] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. [Invention 1176] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. [Invention 1177] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. [Invention 1178] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 8. [Invention 1179] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 11. [Invention 1180] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 12. [Invention 1181] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 20K. [Invention 1182] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 1Peg2, and 1Peg2 is -C(O)-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1183] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 2Peg2, and 2Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1184] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 1Peg2-1Peg2, and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1185] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1186] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 2Peg4, and 2Peg4 is -C(O)-CH2-CH2-(Peg)4-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1187] A hepcidin analog according to any of Invention 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein PEG is 1Peg8, and 1Peg8 is -C(O)-CH2-(Peg)8-N(H)- or -[C(O)-CH2-(OCH2CH2)8-NH]-. [Invention 1188] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 2Peg8, and 2Peg8 is -C(O)-CH2-CH2-(Peg)8-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1189] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 1Peg11, and 1Peg11 is -C(O)-CH2-(Peg)11-N(H)- or -[C(O)-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1190] A hepcidin analog according to any of Invention 1126 to 1174, wherein PEG is 2Peg11, and 2Peg11 is -C(O)-CH2-CH2-(Peg)11-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1191] A hepcidin analog according to any of Invention 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, 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]-. [Invention 1192] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Lys, the -C(O)- of PEG is bound to the Ne of Lys. [Invention 1193] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu. [Invention 1194] A hepcidin analog according to any of the present inventions 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx. [Invention 1195] A hepcidin analog according to any of the Invention 1126 to 1174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Palm, the -N(H)- of PEG is bound to the -C(O)- of Palm. [Invention 1196] A hepcidin analog according to any of inventions 1126 to 1195, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Palm. [Invention 1197] R 2However, the hepcidin analog of any of the inventions 1126 to 1196, which is NH2, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1198] R 2 However, the hepcidin analog of any of the inventions 1126 to 1196, or a pharmaceutically acceptable salt or solvate thereof, is OH. [Invention 1199] R 1 However, C1~C 20 A hepcidin analog according to any of the inventions 1126 to 1196, which is an alkanoyl, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1200] R 1 However, isovaleric acid, a hepcidin analog of any of the inventions 1126 to 1196, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1201] A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The peptide is one of the peptides listed in Table 2, or a dimer thereof. The peptide is cyclized via a disulfide bond between two Cys molecules. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1202] Peptides, or pharmaceutically acceptable salts or solvates thereof, The peptide in question contains or consists of one of the peptides listed in Table 2. The peptide is cyclized via a disulfide bond between two Cys molecules. * indicates that Peg11 is Peg11-OMe. The peptide, or a pharmaceutically acceptable salt or solvate thereof. [Invention 1203] A polynucleotide encoding any of the peptides 1001 to 1202 of this invention. [Invention 1204] A vector comprising the polynucleotide of the present invention 1203. [Invention 1205] A hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or a peptide, according to any of invention 1001 to 1202, A pharmaceutically acceptable carrier, excipient, or vehicle A pharmaceutical composition containing the above. [Invention 1206] A method for binding to ferroportin or inducing the internalization and degradation of ferroportin, The method comprising contacting the ferroportin with at least one hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or a peptide, according to any one of inventions 1001 to 1202. [Invention 1207] A method for treating iron metabolism disorders in those who require it, The method comprising providing, to the subject, an effective amount of a hepcidin analog of any of the inventions 1001 to 1202, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the invention 1205. [Invention 1208] A method for treating a disease or disorder related to dysregulated hepcidin signaling in a person in need thereof, The method comprising providing, to the subject, an effective amount of a hepcidin analog of any of the inventions 1001 to 1202, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the invention 1205. [Invention 1209] The method of the present invention 1207 or 1208, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, spray, sublingual, buccal, parenteral, rectal, vaginal, or topical administration route. [Invention 1210] The method of the present invention 1209, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration. [Invention 1211] Any method of the present invention 1207 to 1210, wherein the disease or disorder is a disease or iron metabolism. [Invention 1212] The method of the present invention 1211, wherein the iron metabolic disorder is an iron overload disorder. [Invention 1213] The method according to any one of the present invention 1207 to 1210, wherein the disease or disorder is hemochromatosis, thalassemia, or polycythemia. [Invention 1214] A method according to any one of the present invention 1207 to 1213, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject up to twice a day, up to once a day, up to once every two days, up to once a week, or up to once a month. [Invention 1215] The method according to any one of the present invention 1207 to 1214, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, is provided to the subject in a dose of about 1 mg to about 100 mg. [Invention 1216] A device comprising a hepcidin analog, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of Invention 1205, for the delivery of the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, of any choice, orally or subcutaneously, to a subject. [Invention 1217] A kit comprising a hepcidin analog of any of Inventions 1001 to 1202, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of Invention 1205, packaged together with a reagent, device, or instructions, or a combination thereof. [Invention 1218] Contains or consists of a peptide, wherein the peptide is: TIFF2026048851000373.tif134152TIFF2026048851000374.tif177151TIFF2026 048851000375.tif226151TIFF2026048851000376.tif198151TIFF202604885100 0377.tif233151TIFF2026048851000378.tif185151TIFF2026048851000379.tif 184151TIFF2026048851000380.tif226151TIFF2026048851000381.tif210151TI Hepcidin analogs, or pharmaceutically acceptable salts or solvates thereof, which are FF2026048851000382.tif216151TIFF2026048851000383.tif163151TIFF2026048851000384.tif209151TIFF2026048851000385.tif170151TIFF2026048851000386.tif201151TIFF2026048851000387.tif202151TIFF2026048851000388.tif185151TIFF2026048851000389.tif92151. [Modes for carrying out the invention]

[0053] Detailed description of the invention The present invention relates, in general terms, to hepcidin analog peptides and methods for producing and using them. In certain embodiments, the hepcidin analog exhibits one or more hepcidin activities. In certain embodiments, the present invention relates to hepcidin peptide analogs comprising one or more peptide subunits that form a cyclized structure by intramolecular bonding, for example, intramolecular disulfide bonds. In certain embodiments, the cyclized structure has increased potency and selectivity compared to non-cyclized hepcidin peptides and their analogs. In certain embodiments, the hepcidin analog peptides of the present invention exhibit an increased half-life compared to hepcidin or conventional hepcidin analogs, for example, when delivered orally.

[0054] Definitions and Terms Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings generally understood by those skilled in the art. Generally, the terms and techniques used in relation to chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0055] As used herein, the following terms have their respective meanings unless otherwise specified.

[0056] Throughout this specification, variations such as “comprise,” “comprises,” or “comprising” mean to include the integer (or component) or group of integers (or components) indicated, but not to exclude any other integer (or component) or group of integers (or components).

[0057] The singular forms "a," "an," and "the" include plural nouns unless otherwise specified by the context.

[0058] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0059] The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domestic animals (e.g., cattle, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats). The term “mammal” refers to any mammalian species such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, and domestic animals.

[0060] As used herein, the term "peptide" broadly refers to a sequence of two or more amino acids linked by peptide bonds. It should be understood that this term does not imply a polymer of amino acids of a specific length, nor is it intended to mean or distinguish whether the polypeptide is produced using recombinant techniques, chemical synthesis, or enzymatic synthesis, or whether it occurs naturally.

[0061] The terms “peptide analog” or “hepcidin analog,” as used herein, broadly refer to peptide monomers and peptide dimers that possess one or more structural features and / or functional activity common to hepcidin or its functional domain. In certain embodiments, peptide analogs include peptides having substantial amino acid sequence identity with hepcidin, e.g., peptides comprising one or more amino acid insertions, deletions, or substitutions compared to the amino acid sequence of wild-type hepcidin, e.g., human hepcidin. In certain embodiments, peptide analogs include one or more additional modifications, such as conjugation to another compound. Any peptide monomer or peptide dimer of the present invention is encompassed by the term “peptide analog.” In certain cases, “peptide analog” may also be referred to herein as “hepcidin analog,” “hepcidin peptide analog,” or “hepcidin analog peptide.”

[0062] When used herein, the terms “sequence identity,” “identity percentage,” “homology percentage,” or any statement including, for example, “sequences that are 50% identical,” refer to the degree to which sequences are identical on a nucleotide-by-nucleotide basis or on an amino acid-by-amino acid basis across a comparison window. Therefore, “sequence identity percentage” may be obtained by comparing two optimally aligned sequences across a comparison window, determining the number of positions in both sequences where the same nucleic acid base (e.g., A, T, C, G, I) or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) are present, obtaining the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to obtain the sequence identity percentage.

[0063] The calculation of sequence similarity or sequence identity between sequences (terms used interchangeably herein) can be performed as follows: To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (for example, gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In certain embodiments, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, or 100% of the length of the reference sequence. Then, amino acid residues or nucleotides are compared at the corresponding amino acid or nucleotide positions. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0064] The identity percentage between two arrays is a function of the number of identical positions shared by the arrays, taking into account the number of gaps that need to be introduced for optimal alignment of the two arrays and the length of each gap.

[0065] The comparison of sequences between two sequences and the determination of the identity percentage can be achieved using mathematical algorithms. In some embodiments, the identity percentage between two amino acid sequences is determined using the Needleman and Wunsch (1970, J. Mol. Biol. 48:444-453) algorithm, which is incorporated into the GAP program in the GCG software package, using a Blossum62 matrix or a PAM250 matrix, and any of the gap weights 16, 14, 12, 10, 8, 6, or 4 and length weights 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the identity percentage between two nucleotide sequences is determined using the GAP program in the GCG software package, using the NWSgapdna.CMP matrix, and any of the gap weights 40, 50, 60, 70, or 80 and length weights 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum62 scoring matrix with a gap penalty 12, a gap length penalty 4, and a frameshift gap penalty 5. The percentage of identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4:11-17), which is incorporated into the ALIGN program (version 2.0), using a PAM120 weighted residue table, a gap length penalty 12, and a gap penalty 4.

[0066] The peptide sequences described herein can be used as "query sequences" to search public databases and identify, for example, other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) by Altschul, et al. (1990, J. Mol. Biol, 215:403-10). Using the NBLAST program, a BLAST nucleotide search can be performed with a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acid molecule of the present invention. Using the XBLAST program, a BLAST protein search can be performed with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein molecule of the present invention. To obtain gapped alignment for comparative purposes, the gapped BLAST described by Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997) can be used. When using BLAST and gapped BLAST programs, you can use the default parameters of each program (e.g., XBLAST and NBLAST).

[0067] As used herein, the term “conservative substitution” refers to the substitution of one or more amino acids with other biologically similar residues. Examples include substitutions of amino acid residues with similar characteristics, such as small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids, and aromatic amino acids. See, for example, the table below. In some embodiments of the present invention, one or more Met residues are substituted with norleucine (Nle), a bioisomer of Met that, in contrast to Met, is not readily oxidized. In some embodiments, one or more Trp residues are substituted with Phe, or one or more Phe residues are substituted with Trp, while in some embodiments, one or more Pro residues are substituted with Npc, or one or more Npc residues are substituted with Pro. Another example of a conservative substitution by residues not typically found in endogenous mammalian peptides and proteins is, for example, the conservative substitution of Arg or Lys with ornithine, canavanine, aminoethylcysteine, or another basic amino acid. In some embodiments, another conserved substitution is the substitution of one or more Pro residues with bhPro, Leu, or D-Npc (isopithecotinic acid). For further information on phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et al., Science 247, 1306-1310, 1990. In the following scheme, conserved amino acid substitutions are grouped by their physicochemical properties: I: neutral, hydrophilic; II: acidic and amide; III: basic; IV: hydrophobic; V: bulky aromatic amino acids. TIFF2026048851000390.tif46128

[0068] In the following scheme, conserved amino acid substitutions are grouped by their physicochemical properties: VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar, X: aromatic. TIFF2026048851000391.tif54128

[0069] As used herein, the terms “amino acid” or “any amino acid” refer to any and all amino acids, including naturally occurring amino acids (e.g., α-amino acids), unnatural amino acids, modified amino acids, and unnatural amino acids. This includes both D-amino acids and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine to form peptide chains and various protein components. These are primarily L-stereoisomers, although several D-amino acids occur in bacterial coats and some antibiotics. Twenty “standard” natural amino acids are listed in the table above. “Non-standard” natural amino acids are pyrrollysine (found in methanogenic organisms and other eukaryotes), selenocysteine ​​(present in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Unnatural" or "non-natural" amino acids are non-proteinogenic amino acids (i.e., amino acids that are not naturally encoded or found in the genetic code) that exist naturally or are chemically synthesized. More than 140 natural amino acids are known, and thousands more combinations are possible. Examples of "unnatural" amino acids include β-amino acids (β 3 and β 2 This includes homoamino acids, proline and pyruvate derivatives, trisubstituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, and N-methylamino acids. Unnatural or non-natural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include one or more groups or chemical moieties that do not naturally exist on the amino acid.

[0070] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are shown from left to right, with the leftmost part of the sequence being the N-terminus of the peptide and the rightmost part being the C-terminus of the peptide. Among the sequences disclosed herein are sequences incorporating a "Hy-" moiety at the amino terminus (N-terminus) and sequences incorporating either an "-OH" moiety or an "-NH2" moiety at the carboxyl terminus (C-terminus). In such cases, unless otherwise indicated, the "Hy-" moiety at the N-terminus of the sequence represents a hydrogen atom corresponding to the presence of a free primary or secondary amino group at the N-terminus, and the "-OH" or "-NH2" moiety at the C-terminus represents a hydroxyl group or an amino group corresponding to the presence of an amide (CONH2) group at the C-terminus, respectively. In each sequence of the present invention, the C-terminal "-OH" moiety may be substituted for the C-terminal "-NH2" moiety, and vice versa. It is further understood that the amino-terminus or carboxy-terminus may be bonded, for example, a covalent bond, particularly when the amino-terminus or carboxy-terminus is bonded to a linker or another chemical part, such as a PEG part.

[0071] As used herein, the term "NH2" refers to the free amino group at the amino terminus of a polypeptide. As used herein, the term "OH" refers to the free carboxyl group at the carboxy terminus of a peptide. Furthermore, as used herein, the term "Ac" refers to acetyl protection through acylation of the C-terminus or N-terminus of a polypeptide.

[0072] As used herein, the term "carboxy" refers to -CO2H.

[0073] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the nomenclature conventions proposed by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as presented in “Nomenclature of α-Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). Where the names and abbreviations of amino acids and aminoacyl residues used herein and in the appended claims differ from these proposals, they are to be clearly stated to the reader. Several abbreviations useful for describing the present invention are defined below in Tables 1A and 1B.

[0074] (Table 1A) Abbreviations for unnatural amino acids and chemical parts TIFF2026048851000392.tif229151TIFF2026048851000393.tif230151TIFF20260488510 00394.tif217151TIFF2026048851000395.tif232151TIFF2026048851000396.tif223151 TIFF2026048851000397.tif228151TIFF2026048851000398.tif231151TIFF20260488510 00399.tif231151TIFF2026048851000400.tif232151TIFF2026048851000401.tif147153

[0075] (Table 1B) Abbreviations for unnatural amino acids and chemical parts TIFF2026048851000402.tif66152TIFF2026048851000403.tif227151TIFF20260488510 00404.tif225151TIFF2026048851000405.tif216151TIFF2026048851000406.tif114152

[0076] Throughout this specification, natural amino acids are designated by their conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine) unless they are referred to by their full names (e.g., alanine, arginine, etc.). For less common or naturally occurring amino acids, unless they are referred to by their full names (e.g., sarcosine, ornithine, etc.), commonly used three-letter or four-letter codes are used for their residues, such as Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (alpha-aminoisobutyric acid), Daba (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), pGlu (pyrogensic acid). It contains glutamic acid, Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (4-aminobutyric acid), bhPro (β-homo-proline), bhPhe (β-homo-L-phenylalanine), bhAsp (β-homo-aspartic acid), Dpa (β,β-diphenylalanine), Ida (iminodiacetic acid), hCys (homocysteine), and bhDpa (β-homo-β,β-diphenylalanine).

[0077] Furthermore, R 1 The sequence can be substituted with isovaleric acid or an equivalent in all parts. In some embodiments, the peptides of the present invention are conjugated with acidic compounds such as isovaleric acid, isobutyric acid, or valeric acid, and the presence of such conjugations is referred to in acidic form. Therefore, in some embodiments, instead of referring to the conjugation of isovaleric acid to the peptide by referring to isovaleroyl, for example, but not limited to isovaleroyl, the present application may refer to such conjugations as isovaleric acid.

[0078] For each of the hepcidine analog formulas provided herein, it is understood that bonds may be indicated by "-" or implied based on the formula and its components. For example, "B7(L1Z)" is understood to include a bond between B7 and L1 if L1 is present, or between B7 and Z if L1 is absent. Similarly, "B5(L1Z)" is understood to include a bond between B5 and L1 if L1 is present, or between B5 and Z if L1 is absent. Furthermore, if both are present, it is understood that the bond exists between L1 and Z. Thus, the definitions of certain substituents such as B7, L1, and J may include "-" before and / or after the defined substituent, but in each case, it is understood that the substituent is bonded to the other substituent via a single bond. For example, "J" may be defined as Lys, D-Lys, Arg, Pro, -Pro-Arg-, etc., and it is understood that J is bonded to Xaa2 and Y1 via a single bond. Therefore, the definition of a substituent is understood to be that it may or may not include "-", but is still bonded to an adjacent substituent.

[0079] As used herein, the term "L-amino acid" refers to a peptide in its "L" isomer form, and conversely, the term "D-amino acid" refers to a peptide in its "D" isomer form. In certain embodiments, the amino acid residues described herein are in their "L" isomer form, but any residue in its "D" isomer form can be substituted with any L-amino acid residue, as long as the desired function is retained by the peptide.

[0080] Unless otherwise indicated, the L-isomer forms of the relevant natural and unnatural amino acids possessing a chiral center are referred to. Where appropriate, the D-isomer forms of amino acids are indicated in the conventional manner by the prefix "D" preceding the conventional three-letter code (e.g., Dasp, (D)Asp or D-Asp; Dphe, (D)Phe or D-Phe).

[0081] As used herein, "lower homolog of Lys" refers to an amino acid that has the structure of lysine but has one or more fewer carbon atoms in its side chain compared to lysine.

[0082] As used herein, “higher homologue of Lys” refers to an amino acid that has the structure of lysine but has one or more additional carbon atoms in its side chain compared to lysine.

[0083] As used herein, the term "DRP" refers to a disulfide-rich peptide.

[0084] As used herein, the term “dimer” broadly refers to a peptide comprising two or more monomeric subunits. A particular dimer contains two DRPs. The dimers of the present invention include homodimers and heterodimers. The monomeric subunits of a dimer may be linked at their C-terminus or N-terminus, or via internal amino acid residues. Each monomeric subunit of a dimer may be linked via the same site, or each may be linked via different sites (e.g., C-terminus, N-terminus, or internal site).

[0085] The terms "isostere replacement" or "isostere substitution" are used interchangeably herein and refer to any amino acid or other analogue moiety that has similar chemical and / or structural properties to a particular amino acid. In certain embodiments, an isostere substitution is a conservation substitution with a native or non-native amino acid.

[0086] As used herein, the term "cyclization" refers to a reaction in which part of a polypeptide molecule is linked to another part of a polypeptide molecule, forming a ring closure by disulfide crosslinking or other similar bonding.

[0087] As used herein, the term "subunit" refers to one of a pair of polypeptide monomers that combine to form a dimeric peptide composition.

[0088] As used herein, the term "linker moiety" broadly refers to a chemical structure that can link or bond two peptide monomer subunits to form a dimer.

[0089] In the context of this invention, the term “solvate” refers to a defined stoichiometric complex formed between a solute (e.g., a hepcidin analog or a pharmaceutically acceptable salt thereof according to this invention) and a solvent. The solvent in this context may be, for example, water, ethanol, or another pharmaceutically acceptable species, typically a small molecule organic species, such as water, ethanol, or acetic acid or lactic acid. When the solvent in question is water, such a solvate is usually referred to as a hydrate.

[0090] As used herein, “iron metabolism disorders” include diseases in which abnormal iron metabolism directly causes the disease, or in which blood iron levels are dysregulated to cause the disease, or in which iron dysregulation is a consequence of another disease, or in which the disease can be treated by regulating iron levels. More specifically, iron metabolism disorders as used herein include iron overload disorders, iron deficiency disorders, disorders of iron biodistribution, other disorders of iron metabolism, and other disorders potentially related to iron metabolism. Iron metabolism disorders include hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemomodoverin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusion-induced iron overload, thalassemia, intermediate thalassemia, alpha-thalassemia, sideroblastic anemia, porphyria, late-onset cutaneous porphyria, African iron overload, hyperferritinemia, ceruloplasmin deficiency, transferrinemia, congenital erythrocytosis anemia, anemia due to chronic disease, anemia due to inflammation, anemia due to infection, and hypochromasia. This includes microcytic anemia, sickle cell anemia, polycythemia vera (primary and secondary), myelodysplasia, pyruvate kinase deficiency, iron deficiency anemia, iron-refractory iron deficiency anemia, anemia in chronic kidney disease, erythropoietin resistance, iron deficiency in obesity, other anemias, benign or malignant tumors that overproduce or induce hepcidin, hepcidin excess, ataxia Friedreich, stunted syndrome, Haller-Volden-Spats disease, Wilson's disease, pulmonary hemosiderinosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis, pica, chronic renal failure, insulin resistance, diabetes mellitus, atherosclerosis, neurodegenerative diseases, multiple sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease.

[0091] In some embodiments, the diseases and disorders are associated with iron overload disorders such as iron hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemomodoverin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusion-induced iron overload, thalassemia, thalassemia intermediates, alpha-thalassemia, sickle cell disease, polycythemia vera (primary and secondary), myelodysplasia, and pyruvate kinase deficiency.

[0092] In some embodiments, the hepcidin analogs of the present invention are used to treat diseases and disorders not typically identified as iron-related. For example, hepcidin is highly expressed in mouse pancreas, suggesting that diabetes mellitus (type I or II), insulin resistance, impaired glucose tolerance, and other disorders may be ameliorated by treating underlying iron metabolic disorders. See Ilyin, G. et al. (2003) FEBS Lett. 542 22-26, incorporated herein by reference. Thus, the peptides of the present invention may be used to treat these diseases and conditions. Those skilled in the art can readily determine whether a given disease can be treated with the peptides of the present invention using methods known in the art, including assays known in the art, such as the WO2004 / 092405 assay incorporated herein by reference, and assays that monitor hepcidin, hemoduverin, or iron levels and expression, as described in U.S. Patent No. 7,534,764, incorporated herein by reference.

[0093] In certain embodiments of the present invention, iron metabolism disorders are iron overload disorders, including hereditary hemochromatosis, iron-loaded anemia, alcoholic liver disease, and chronic hepatitis C.

[0094] The term "pharmaceutically acceptable salt," as used herein, refers to a salt or zwitterionic form of the compound of the present invention that is water-soluble, oil-soluble, or dispersible, suitable for the treatment of a disease without excessive toxicity, irritation, or allergic reactions, conforms to a reasonable benefit / risk ratio, and is effective for its intended use. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the amino group with a suitable acid. Typical acid addition salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, and mesitylene. Examples of amino acids include ruhonates, methanesulfons, naphthylenesulfons, nicotinates, 2-naphthalenesulfons, oxalates, pamoates, pectins, persulfates, 3-phenylproprionate, picrates, pivalates, propions, succinates, tartrates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfons, and undecanoates. Furthermore, the amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl bromide and phenethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts are preferably selected from, for example, acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts, and acetate salts.Examples of basic salts include salts in which the cation is selected from alkali metal cations such as sodium or potassium ions, alkaline earth metal cations such as calcium or magnesium ions, and substituted ammonium ions such as N(R1)(R2)(R3)(R4)+ type ions (where R1, R2, R3, and R4 independently typically represent hydrogen, optionally substituted C1-6-alkyl, or optionally substituted C2-6-alkenyl). Examples of relevant C1-6-alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl groups. Examples of possible relevant C2-6-alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66:2 (1977). For a review of suitable salts, see also Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Other suitable base salts are formed from bases that form non-toxic salts. Typical examples include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc. Hemisalts of acids and bases, such as hemisulfate salts and hemicalcium salts, can also be formed.

[0095] The term "N(alpha)methylation," as used herein, refers to the methylation of an alphaamine of an amino acid, also commonly known as N-methylation.

[0096] The terms "symmetric methylation" or "Arg-Me-sym," as used herein, describe the symmetric methylation of two nitrogen atoms of the guanidine group of arginine. Furthermore, the terms "asym methylation" or "Arg-Me-asym" describe the methylation of a single nitrogen atom of the guanidine group of arginine.

[0097] The term "acylated organic compound," as used herein, refers to a variety of compounds having a carboxylic acid functional group used to acylate the N-terminus of an amino acid subunit before forming a C-terminal dimer. Non-limiting examples of acylated organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentanecarboxylic acid, 3,3,3-trifluoropropeonic acid, 3-fluoromethylbutyric acid, and tetrahedro-2H-pyran-4-carboxylic acid.

[0098] The term "alkyl" includes linear or branched, acyclic or cyclic saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Typical saturated linear alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Typical saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl. Typical saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Typical unsaturated cyclic alkyls include, but are not limited to, cyclopentenyl and cyclohexenyl.

[0099] As used herein, “therapeutic effective dose” of the peptide agonist of the present invention is intended to describe a sufficient amount of the peptide agonist to treat any hepcidin-related disease, including but not limited to any of the diseases and disorders described herein (e.g., iron metabolic disorders). In particular embodiments, the therapeutic effective dose achieves a desired benefit / risk ratio applicable to any medical treatment.

[0100] hepcidin peptide analog The present invention provides hepcidin peptide analogs (collectively referred to as "hepcidin analogs") that may be monomers or dimers.

[0101] In some embodiments, the hepcidin analogs of the present invention bind to ferroportin, for example, human ferroportin. In certain embodiments, the hepcidin analogs of the present invention bind specifically to human ferroportin. As used herein, “specifically bind” means a preferential interaction of a specific binder with a given ligand over other agents in the sample. For example, a specific binder that specifically binds to a given ligand binds to the given ligand in an observable amount or degree that exceeds the amount or degree of any nonspecific interactions with other components in the sample under preferred conditions. Preferred conditions are those that allow interaction between a given specific binder and a given ligand. These conditions include pH, temperature, concentration, solvent, incubation time, etc., and may differ between given specific binder-ligand pairs, but can be readily determined by those skilled in the art. In some embodiments, the hepcidin analogs of the present invention bind to ferroportin with higher specificity than a hepcidin reference compound (for example, any one of the hepcidin reference compounds provided herein). In some embodiments, the hepcidin analogs of the present invention exhibit ferroportin specificity that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or 10,000% higher than a hepcidin reference compound (e.g., any one of the hepcidin reference compounds provided herein). In some embodiments, the hepcidin analogs of the present invention exhibit ferroportin specificity that is at least about 5 times, or at least about 10 times, 20 times, 50 times, or 100 times higher than a hepcidin reference compound (e.g., any one of the hepcidin reference compounds provided herein).

[0102] In certain embodiments, the hepcidin analogs of the present invention exhibit hepcidin activity. In some embodiments, the activity is in vitro or in vivo activity, e.g., in vivo or in vitro activity as described herein. In some embodiments, the hepcidin analogs of the present invention exhibit at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or more than 99% of the activity exhibited by a hepcidin reference compound (e.g., any one of the hepcidin reference compounds provided herein).

[0103] In some embodiments, the hepcidin analogs of the present invention exhibit at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or more than 99% of the ferroportin-binding ability shown by the hepcidin reference compound. In some embodiments, the hepcidin analogs of the present invention exhibit a lower EC for binding to ferroportin (e.g., human ferroportin) compared to the hepcidin reference compound. 50 or IC 50 (i.e., higher binding affinity). In some embodiments, the hepcidin analogs of the present invention exhibit an EC at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, or 1000% lower EC than the hepcidin reference compound in a ferroportin competitive binding assay. 50 It has.

[0104] In certain embodiments, the hepcidin analogs of the present invention exhibit increased hepcidin activity compared to the hepcidin reference compound. In some embodiments, the activity is in vitro or in vivo activity, e.g., in vivo or in vitro activity as described herein. In certain embodiments, the hepcidin analogs of the present invention exhibit hepcidin activity 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or more than 200 times greater than the hepcidin reference compound. In certain embodiments, the hepcidin analogs of the present invention exhibit at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or more than 99%, 100%, 200%, 300%, 400%, 500%, 700%, or 1000% activity compared to the hepcidin reference compound.

[0105] In some embodiments, the peptide analogs of the present invention exhibit at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 99%, 100%, 200%, 300%, 400%, 500%, 700%, or more than 1000% in in vitro activity for inducing the degradation of human ferroportin protein compared to a hepcidin reference compound, the activity of which is measured according to the method described herein.

[0106] In some embodiments, the peptides or peptide dimers of the present invention exhibit at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99%, 100%, 200%, 300%, 400%, 500%, 700%, or greater than 1000% in in vivo activity that induces a reduction in free plasma iron in an individual, compared to a hepcidin reference compound, and the activity is measured according to the method described herein.

[0107] In some embodiments, the activity is in vitro or in vivo activity, for example, in vivo or in vitro activity as described herein. In certain embodiments, the hepcidin analogs of the present invention are 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200 times more potent than the hepcidin reference compound, or at least about 10%, 20%, 30%, 40%, 50%, The activity is 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, or 1000% greater, and the activity is either in vitro activity for inducing the degradation of ferroportin, as measured, for example, according to the examples herein, or in vivo activity for reducing free plasma iron, as measured, for example, according to the examples herein.

[0108] In some embodiments, the hepcidin analogs of the present invention mimic the hepcidin activity of Hep25, a bioactive human 25-amino acid form, and are referred to herein as “minihepcidins.” As used herein, in certain embodiments, a compound having “hepcidin activity” (e.g., a hepcidin analog) means that the compound has the ability to reduce plasma iron concentration in a subject (e.g., mouse or human) in a dose-dependent and time-dependent manner when administered to the subject (e.g., parenterally by injection or orally). See, for example, Rivera et al. (2005), Blood 106:2196-9. In some embodiments, the peptides of the present invention reduce the plasma iron concentration in a subject by at least about 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, or by at least about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 99%.

[0109] In some embodiments, the hepcidin analogs of the present invention have in vitro activity assayed by their ability to induce internal translocation and degradation of ferroportin in ferroportin-expressing cell lines as taught in Nemeth et al. (2006) Blood 107:328-33. In some embodiments, in vitro activity is measured by dose-dependent loss of fluorescence in cells engineered to show ferroportin fused to green fluorescent protein, as described in Nemeth et al. (2006) Blood 107:328-33. Aliquots of cells are incubated for 24 hours at gradient concentrations of a reference preparation of Hep25 or minihepcidin. As provided herein, EC 50 The value is provided as the concentration of a given compound (e.g., the hepcidin analog peptide or peptide dimer of the present invention) that causes 50% of the maximum fluorescence loss produced by the reference compound. The EC of the Hep25 preparation in this assay. 50 The EC2 is in the range of 5 to 15 nM, and in certain embodiments, the preferred hepcidin analog of the present invention exhibits an EC2 of approximately 1,000 nM or less in an in vitro activity assay. 50 In certain embodiments, the hepcidin analogs of the present invention have an IC value less than one of the following in an in vitro activity assay (e.g., as described in Nemeth et al. (2006) Blood 107:328-33 or the examples herein): about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, or 500 nM. 50 or EC 50 It has. In some embodiments, the hepcidin analog or the biotherapeutic composition (for example, any one of the pharmaceutical compositions described herein) has an IC of about 1 nM or less. 50 or EC 50 It has a value.

[0110] Other methods known in the art may be used to calculate the hepcidin activity and in vitro activity of the hepcidin analogs according to the present invention. For example, in certain embodiments, the in vitro activity of the hepcidin analog or reference peptide is measured by their ability to internalize cellular ferroportin, which is determined by immunohistochemistry or flow cytometry using an antibody that recognizes the extracellular epitope of ferroportin. Alternatively, in certain embodiments, the in vitro activity of the hepcidin analog or reference peptide is measured by their dose-dependent ability to inhibit iron efflux from ferroportin-expressing cells pre-packed with radioactive or stable isotopes of iron, as described in Nemeth et al. (2006) Blood 107:328-33.

[0111] In some embodiments, the hepcidin analogs of the present invention exhibit increased stability (e.g., measured by half-life, proteolytic rate) compared to the hepcidin reference compound. In certain embodiments, the stability of the hepcidin analogs of the present invention is increased by at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200 times compared to the hepcidin reference compound, or by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, or 500%. In some embodiments, the stability is the stability described herein. In some embodiments, stability is plasma stability, which is optionally measured, for example, according to the method described herein. In some embodiments, stability is stability when delivered orally.

[0112] In certain embodiments, the hepcidin analogs of the present invention exhibit a longer half-life than the hepcidin reference compound. In certain embodiments, the hepcidin analogs of the present invention exhibit a half-life of at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 12 hours, at least about 18 hours, at least about 1 day, at least about 2 days, at least about 4 days, at least about 7 days, at least about 10 days under given conditions (e.g., temperature, pH). The half-lives are at least about two weeks, at least about three weeks, at least about one month, at least about two months, at least about three months or more, or any intermediate half-live or intermediate range, about five minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about one hour, about two hours, about three hours, about four hours, about five hours, about six hours, about twelve hours, about eighteen hours, about one day, about two days, about four days, about seven days, about ten days, about two weeks, about three weeks, about one month, about two months, about three months or more, or any intermediate half-live or intermediate range. In some embodiments, the half-life of the hepcidin analog of the present invention is extended by conjugation to one or more lipophilic substituents or half-life extending portions, for example, any of the lipophilic substituents or half-life extending portions disclosed herein. In some embodiments, the half-life of the hepcidin analog of the present invention is extended by conjugation to one or more polymer moieties, for example, any of the polymer moieties or half-life-extending moieties disclosed herein. In certain embodiments, the hepcidin analog of the present invention has the above half-life under given conditions where the temperature is about 25°C, about 4°C, or about 37°C and the pH is physiological pH or about 7.4.

[0113] In certain embodiments, the hepcidin analog of the present invention, comprising a conjugated half-life extension portion, has an increased serum half-life after oral, intravenous, or subcutaneous administration compared to the same analog lacking the conjugated half-life extension portion. In certain embodiments, the serum half-life of the hepcidin analog of the present invention after oral, intravenous, or subcutaneous administration is at least 12 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 48 hours, at least 72 hours, or at least 168 hours. In certain embodiments, this is 12–168 hours, 24–168 hours, 36–168 hours, or 48–168 hours.

[0114] In certain embodiments, the hepcidin analog of the present invention, for example, a hepcidin analog comprising a conjugated half-life extension portion, results in a decrease in serum iron concentration after oral, intravenous, or subcutaneous administration to a subject. In certain embodiments, the subject's serum iron concentration decreases to less than 10%, less than 20%, less than 25%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, or less than 90% of the serum iron concentration without administration of the hepcidin analog to the subject. In certain embodiments, the decreased serum iron concentration is maintained for at least 1 hour, at least 4 hours, at least 10 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours after administration to the subject. In certain embodiments, this is maintained for 12–168 hours, 24–168 hours, 36–168 hours, or 48–168 hours. In one embodiment, the target serum iron concentration is reduced to less than 20% approximately 4 hours or 10 hours after administration to the target, for example, intravenously, or orally, or subcutaneously. In another embodiment, the target serum iron concentration is reduced to less than 50% or 60% approximately 24 to 30 hours after administration, for example, intravenously, or or subcutaneously.

[0115] In some embodiments, the half-life is measured in vitro using any preferred method known in the art, for example, in some embodiments, the stability of the hepcidin analog of the present invention is determined by incubating the hepcidin analog with preheated human serum (Sigma) at 37°C. Typically, samples are taken at various time points up to 24 hours, the hepcidin analog is separated from the serum protein, and then the stability of the sample is analyzed by analyzing the presence of the hepcidin analog of interest using LC-MS.

[0116] In some embodiments, the stability of the hepcidin analog is measured in vivo using any preferred method known in the art. For example, in some embodiments, the stability of the hepcidin analog is determined in vivo by administering the peptide or peptide dimer to a subject such as a human or any mammal (e.g., a mouse), and the sample is then taken from the subject by blood collection at various time points, typically up to 24 hours. The sample is then analyzed as described above with respect to an in vitro method for measuring the half-life. In some embodiments, the in vivo stability of the hepcidin analog of the present invention is determined by the method disclosed in the examples herein.

[0117] In some embodiments, the present invention provides hepcidin analogs described herein, wherein the hepcidin analog exhibits improved solubility or improved aggregation properties compared to a hepcidin reference compound. Solubility can be determined by any preferred method known in the art. In some embodiments, preferred methods known in the art for determining solubility include incubating the peptide in various buffers (acetate pH 4.0, acetate pH 5.0, phosphate / citrate (Phos / Citrate) pH 5.0, citrate phosphate (Phos Citrate) pH 6.0, phosphate pH 6.0, phosphate pH 7.0, phosphate pH 7.5, strong PBS pH 7.5, Tris pH 7.5, Tris pH 8.0, glycine pH 9.0, water, acetic acid (pH 5.0 and others known in the art)) and testing for aggregation or solubility using standard techniques. These include, for example, measuring visible precipitation, dynamic light scattering, circular dichroism, and surface hydrophobicity, and fluorescent dyes for detecting aggregation or fibrillation. In some embodiments, improved solubility means that the peptide (e.g., the hepcidin analog of the present invention) is more soluble in a given liquid than the hepcidin reference compound.

[0118] In certain embodiments, the present invention provides hepcidin analogs described herein that exhibit solubility in a particular solution or buffer, for example, in water or buffers known in the art or disclosed herein, at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200 times greater than that of a hepcidin reference compound, or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, or 500% greater.

[0119] In certain embodiments, the present invention provides hepcidin analogs that exhibit reduced aggregation, where the aggregation of peptides in solution is at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200 times lower than that of a hepcidin reference compound in certain solutions or buffers, for example, water or buffers known in the art or disclosed herein.

[0120] In some embodiments, the present invention provides hepcidin analogs described herein that exhibit less degradation (i.e., greater degradation stability) than, for example, a hepcidin reference compound, by more than 10% or about 10%, more than 20% or about 20%, more than about 30% or about 30%, more than about 40% or about 40%, or more than 50% or about 50%. In some embodiments, degradation stability is determined by any preferred method known in the art. In some embodiments, preferred methods known in the art for determining degradation stability include the method described in Hawe et al J Pharm Sci, VOL.101, NO.3, 2012, pp. 895-913, which is incorporated herein in whole. Such methods are used in some embodiments to select potent sequences having an extended shelf life.

[0121] In some embodiments, the hepcidin analogs of the present invention are produced by synthesis. In other embodiments, the hepcidin analogs of the present invention are produced by recombinant synthesis.

[0122] The various hepcidin analog monomers and dimeric peptides of the present invention may be constructed solely from natural amino acids. Alternatively, these hepcidin analogs may include, but are not limited to, modified amino acids, non-natural or non-natural amino acids. In certain embodiments, the modified amino acids include natural amino acids that have been chemically modified to include one or more groups or chemical moieties that do not naturally exist on the amino acid. The hepcidin analogs of the present invention may further include D-amino acids. Furthermore, the hepcidin analog peptide monomers and dimers of the present invention may include amino acid analogs. In certain embodiments, the peptide analogs of the present invention include any of those described herein in which one or more natural amino acid residues of the peptide analog are substituted with non-natural or non-natural amino acids, or D-amino acids.

[0123] In certain embodiments, the hepcidin analogs of the present invention include one or more modified or unnatural amino acids. For example, in certain embodiments, the hepcidin analogs include one or more of the following: Daba, Dapa, Pen, Sar, Cit, Cav, HLeu, 2-Nal, 1-Nal, d-1-Nal, d-2-Nal, Bip, Phe(4-OMe), Tyr(4-OMe), βhTrp, βhPhe, Phe(4-CF3), 2-2-indan, 1-1-indan, cyclobutyl, βhPhe, hLeu, Gla, Phe(4-NH2), hPhe, 1-Nal, Nle, 3-3-diPhe, cyclobutyl-Ala, Cha, Bip, β-Glu, Phe(4-Guan), homoamino acids, D-amino acids, and various N-methylated amino acids. Those skilled in the art will understand that various other substitutions of natural amino acids with other modified or non-natural amino acids may be made to achieve similar desired results, and that such substitutions are within the scope of the teachings and spirit of the present invention.

[0124] The present invention includes, for example, any of the hepcidin analogs described herein, either in free or salt form.

[0125] The compounds described herein include isotope-labeled compounds, which are identical to the compounds described in the various formulas and structures presented herein, except that one or more atoms are substituted with atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into these compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 1 3C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Examples include Cl. Specific isotope-labeled compounds described herein, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in tissue distribution assays of drugs and / or substrates. Furthermore, deuterium, i.e. 2 Substitution with isotopes such as H can provide certain therapeutic benefits resulting from higher metabolic stability, for example, an increased in vivo half-life or reduced dosage requirements. In certain embodiments, the compound is isotope-substituted with deuterium. In more specific embodiments, the most unstable hydrogen is substituted with deuterium.

[0126] The hepcidin analog of the present invention comprises either a peptide monomer or dimer described herein, linked to a linker moiety containing a specific linker moiety described herein.

[0127] The hepcidin analogs of the present invention include peptides, such as monomers or dimers, comprising a peptide monomer subunit having at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 98%, or at least 99% amino acid sequence identity with any of the amino acid sequences shown in Tables 2 and 3 of the hepcidin analog peptide sequence described herein (e.g., any one of the peptides disclosed herein).

[0128] In certain embodiments, the monomeric subunit of the peptide analog or dimeric peptide analog of the present invention comprises or consists of 7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues, and optionally one or more additional non-amino acid moieties, such as conjugated chemical moieties, such as half-life extension moieties, PEG or linker moieties. In certain embodiments, the monomeric subunit of the hepcidin analog comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acid residues. In certain embodiments, the monomeric subunit of the hepcidin analog of the present invention comprises or consists of 10 to 18 amino acid residues and optionally one or more additional non-amino acid moieties, such as a conjugated chemical moiety, such as a PEG or linker moiety. In various embodiments, the monomeric subunit comprises or consists of 7 to 35 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues. In any particular embodiment of the various formulas described herein, X comprises or consists of 7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues.

[0129] In certain embodiments, the hepcidin analogs or dimers of the present invention do not contain any of the compounds described in PCT / US2014 / 030352 or PCT / US2015 / 038370.

[0130] Peptideheptidin analog In certain embodiments, the hepcidin analogs of the present invention comprise a single peptide subunit optionally conjugated to a half-life extension portion. In certain embodiments, these hepcidin analogs form a cyclized structure via intramolecular disulfide or other bonds.

[0131] In one embodiment, the present invention relates to formula (I): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula I, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either -NH2 or -OH; Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp; Each Xaa1 and Xaa2 is independently Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is the aminohexanoic acid moiety and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence number 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -His-(D)Phe-Arg-Trp-Cys- (Sequence ID 140) It is either not present or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen, and Y2 is an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I optionally contains one or more R 1PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0132] In one embodiment, the present invention relates to formula (I'): R 1 -Xbb1-Thr-X3-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (I') A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Asp, isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, bGlu, Gla, or Glp; X3 is His or substitute His; Each Xaa1 and Xaa2 is independently Ala, Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is non-existent, Lys, D-Lys, (D)Leu, (D)Ala, a-Me-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and 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 from 1 to 100K; Z is the half-life extension portion; J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, where each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly; Y1 is Abu, Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R 1PEGylated in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; However, if Xbb1 is Asp, R 1 C2~C 20 It is Alkenoil.

[0133] In one embodiment, X1 is Asp, and R 1 C2~C 20 It is Alkenoil.

[0134] In one embodiment, Xbb1 is (D)Glu or (D)IsoGlu.

[0135] In one embodiment, Xbb1 is iso-Asp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp.

[0136] In one embodiment, B1 is Dpa.

[0137] In one embodiment, Xaa1 is B5(L1Z), where B5 is Lys, D-Lys, Dap, or Dap-Dap, and Xaa2 is B7, where B7 is either Glu or absent.

[0138] In one embodiment, Pro or NPC.

[0139] In one embodiment, X7 is Ile.

[0140] In one embodiment, B9 is Phe or bhPhe.

[0141] In one embodiment, J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, each amino acid independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly.

[0142] In one embodiment, J is Arg, Lys, D-Lys, Spiropip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SALES) 139 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -Pro-Lys(Ac)-, -Pro-(D)Lys(Ac)-, -Pro-Arg-Ser-Lys(Ac)-(SEQ ID NO: 250),-Sar-(SEQ ID NO: 251), -Pro-Lys(Ac)-, -Pro-(D)Lys(Ac)-, -Pro-Arg-Ser-Lys(Ac)-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-G 141 ), -Pro-Arg-Ser-Lys(Ac)-Sar-(Array No. 142 ), -Pro-Arg-Ser-Lys(Ac)-Gly- (Sequence ID 143) ,-hydroxyPro-Arg-Ser-Lys-Gly-(SEQ ID NO: 144 ), -Pro-MeArg-Ser-Lys-Gly- (Sequence ID 145) ,-Pro-Arg-MeSer-Lys-Gly-(Array No. 146)、- Pro-Lys(Ac)-Ser-Lys(Ac)- (Sequence ID 147) , -Pro-Lys(Ac)-Ser-Lys(Ac)-Gly- (Sequence ID 148) , -Pro-Lys(Ac)-Ser-Lys(Ac)-Gly- (Sequence ID 148) , -Pro-Lys(Ac)-Ser-Lys(Ac)-Sar- (Sequence ID 149) 、-Pro-Arg-Ser-MeLys-Gly (Sequence ID 150) It is either present or absent, or J is any amino acid.

[0143] In one embodiment, J is Arg, Lys, D-Lys, Spiropip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys-(SALES) 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or none of the above, or J is any amino acid.

[0144] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0145] In one embodiment, Xaa1 is B5, where B5 is non-existent, Lys, or D-Lys, and Xaa2 is B7(L1Z), where B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0146] In another embodiment, Xaa1 is B5(L1Z), where B5 is Lys or D-Lys, and Xaa2 is B7, where B7 is Glu or absent.

[0147] In one embodiment, the present invention is given by formula (AI): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (AI) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula I, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (I); B7 is either Lys or D-Lys; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, then B5 is not Lys; iv) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 does not exist; v) If the peptide is a peptide dimer, the peptide dimer a) Through the linker portion, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes the half-life extension portion.

[0148] In one embodiment, with respect to the peptide of formula (AI), R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl, and R 2 However, it is either -NH2 or -OH; B1 and B6 are independent of each other. i) Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, or D-Phe, ii) 2-Nal, 1-Nal, D-1-Nal, D-2-Nal, 3,3-diphenylGly, Tic, Bip, Trp, bhTrp, hPhe, or Tyr(Me), iii) Substitutions Phe, bhPhe, Trp, or bhTrp; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, or Pen; B4 is Gly, N-substituted Gly, Ile, (Me)Ile, Val, Leu, or NLeu; B5 is Lys, D-Lys, Orn, homoser, Gln, Lys(Ac), Ile, Abu, Leu, or Nleu; and B7 is a lower or higher homolog of Lys; L1 is either absent, or is isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is the aminohexanoic acid portion, and L1 is the N of B7. ε It is coupled to Z, which is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence number 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or none thereof; Y1 is Cys, homocys, or Pen; and Y2 is an amino acid or none thereof.

[0149] In one embodiment, with respect to the peptide of formula (AI), R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl, and R 2 However, it is either -NH2 or -OH; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, or Pen; B4 is Gly, N-substituted Gly, Ile, (Me)Ile, Val, Leu, or NLeu; B5 is non-existent, Lys, or D-Lys; and B7 is a lower or higher homolog of Lys, a-MeLys, or D-Lys; L1 is either absent, or is isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and L1 is the N of B7. ε It is bonded to Z, the half-life extension portion, and J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence ID) 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), -His-(D)Phe-Arg-Trp- (Sequence ID 137) It is either true or false, or J is any amino acid, Y1 is Cys, homocys, NMeCys, aMeCys, or Pen, and Y2 is either an amino acid or false.

[0150] In certain embodiments, B5 is D-Lys.

[0151] In one embodiment, the present invention is given by formula (BI): R 1 -Xbb1-Thr-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (BI) A hepcidin analog containing the peptide, or a peptide dimer containing two peptides according to formula BI, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 , R 2B1-B6, L1, Z, J, Y1, and Y2 are as shown in formula (I); Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (array array) 136 ) is either true or does not exist.

[0152] In one embodiment, with respect to the peptide of formula (BI), R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either -NH2 or -OH; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, or Pen; B4 is Gly, N substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; B5 is either Lys or D-Lys; B7 is either Glu or does not exist; L1 is either absent, or is isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100K. Ahx is the aminohexanoic acid portion, and L1 is the N of B7. ε It is connected; Z is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO. 136 ), -Pro-Arg-Ser-Lys-Sar-(sequence number 250), -Pro-Arg-Ser-Lys-Gly-(sequence number 251), or none of these; Y1 is Cys, homocys, or Pen; Y2 is either an amino acid or absent; The half-life extension portion is C 10 ~C 21 It is an alcanoyl; Dpa is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, βhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Npc is nipecotinic acid, bhTrp is L-β-homotryptophan, Nal is naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted β-hPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted β-hTrp is N-methyl-Lb-homotypephan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu. Here: i) The peptide of formula I is optionally R 1 PEGylation is performed in B1, B2, B3, B4, B6, B7, J, Y1, Y2, and R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0153] In one embodiment, R 1 is hydrogen, or C1~C 20 It is Alkanoyl.

[0154] In one embodiment, R 1 R is hydrogen, isovaleric acid, isobutyric acid, or acetyl. In certain embodiments, R 1 It is isovaleric acid.

[0155] In one embodiment, B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC.

[0156] In one embodiment, B3 is Cys. In another embodiment, B3 is homocystic Cys.

[0157] In one embodiment, B4 is Ile.

[0158] In one embodiment, B5 does not exist.

[0159] In another embodiment, B5 is Lys or D-Lys.

[0160] In another embodiment, the peptide is cyclized via a disulfide bond between B3 and Y1.

[0161] In one embodiment, Y1 is Cys or homocys.

[0162] In one embodiment, the half-life extension portion is C 14 ~C 20 It is Alkanoyl.

[0163] In one embodiment, B7 is a lower homolog of Lys. In another embodiment, B7 is a higher homolog of Lys. In a further embodiment, B7 is homoLys, a-MeLys, or abu. In a particular embodiment, B7 is Lys or D-Lys.

[0164] In another embodiment, B7 is Dapa.

[0165] In another embodiment, B2 is Pro or NPC, B3 is Cys, B4 is Ile, and B6 is Phe, bhPhe, or 2Pal.

[0166] In one embodiment, a lower homolog of Lys is 2,3-diaminopropanoic acid or 2,4-diaminobutyric acid. In another embodiment, a lower homolog of Lys is L-2,3-diaminopropanoic acid. In yet another embodiment, a lower homolog of Lys is D-2,3-diaminopropanoic acid. In yet another embodiment, a lower homolog of Lys is L-2,4-diaminobutyric acid. In yet another embodiment, a lower homolog of Lys is D-2,4-diaminobutyric acid.

[0167] In one embodiment, a higher homolog of Lys is homoLys or L-2,6-diaminohexanoic acid. In another embodiment, a higher homolog of Lys is D-homoLys or D-2,6-diaminohexanoic acid.

[0168] In certain embodiments, the peptide is of formula II or III, R 1 -Asp-Thr-His-B1-B2-B3-Ile-B5-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (II) R 1 -Asp-Thr-His-B1-B2-B3-Ile-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-B6-B7-J-Y1-Y2-R 2 (III) Alternatively, a peptide dimer containing two peptides according to formula (II) or (III), or a pharmaceutically acceptable salt thereof.

[0169] In one embodiment, B2 is Pro, D-Pro, or bhPro. In a particular embodiment, B2 is Pro.

[0170] In one embodiment, B3 is Cys. In another embodiment, B3 is Pen. In yet another embodiment, B3 is homocystic.

[0171] In a more specific embodiment, with respect to the peptide by formula AI, B7(L1Z) is -N(H)C[CH2(CH2CH2CH2) m The expression is N(H)L1Z](H)-C(O)-, where m is either 0 or 1.

[0172] In one embodiment, with respect to the peptide described in formula AI, B7(L1Z) is -N(H)C[CH2N(H)L1Z](H)-C(O)-.

[0173] In the most specific embodiment, with respect to the peptide by formula AI, B7(L1Z) is -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-.

[0174] In certain embodiments, the present invention relates to formula IV or V: R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (IV), or R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (V) The present invention provides a hepcidin analog containing a peptide, or a peptide dimer thereof, or a pharmaceutically acceptable salt thereof. During the ceremony: R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for formula (I), B1 is F or Dpa, B5 is (D)Lys, and B6 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), bhPhe, or 2Pal; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (array array) 136 ) is either true or does not exist.

[0175] In a more specific embodiment, B5 is (D)Lys.

[0176] In certain embodiments, the peptide is of formula VI or VII: R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (VI), or R 1 -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (VII) This is due to, or its peptide dimer, or its pharmaceutically acceptable salt. During the ceremony: R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for equation (I); B1 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), or Dpa, and B6 is Phe, bhPhe, or 2Pal.

[0177] In a more specific embodiment, B1 is Phe, Phe(4-F), Phe(4-CF3), or Phe(2,3,5-trifluoro). In a more specific embodiment, B1 is Phe. In another embodiment, B1 is Dpa. In yet another embodiment, B1 is b-hPhe.

[0178] In certain embodiments, the peptide is of formula VIII or IX: R 1 -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (VIII), or R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (IX) This is due to, or its peptide dimer, or its pharmaceutically acceptable salt. During the ceremony: R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for formula (I), and B6 is Phe(4-F), Phe(4-CF3), or Phe(2,3,5-trifluoro), bhPhe, 2Pal.

[0179] In a more specific embodiment, B6 is Phe. In another embodiment, B6 is bhPhe.

[0180] In one embodiment, the peptide is of formula Xa, Xb, Xc, or Xd: R 1 -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xa) R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xb) R 1-Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xc) R 1 -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xd) This is due to, or its peptide dimer, or its pharmaceutically acceptable salt. During the ceremony: R 1 , R 2 L1, Z, J, Y1, and Y2 are as shown in formula (I).

[0181] In one embodiment, with respect to the peptide of the present invention, the Pro in -Asp-Thr-His-B1-Pro-Cys-Ile-B5-B6- is replaced with dPro or Npc.

[0182] In certain embodiments, with respect to the peptide of the present invention, the peptide is cyclized via a disulfide bond between two Cys molecules.

[0183] In one embodiment, with respect to the peptide of the present invention, -N(H)C[CH2N(H)L1Z](H)-C(O)- is an L-amino acid. In another embodiment, with respect to the peptide of the present invention, -N(H)C[CH2N(H)L1Z](H)-C(O)- is a D-amino acid.

[0184] In one embodiment, with respect to the peptide of the present invention, -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)- is an L-amino acid. In another embodiment, with respect to the peptide of the present invention, -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)- is a D-amino acid.

[0185] In one embodiment, each Xaa1 and Xaa2 is independently Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac).

[0186] In one embodiment, Xaa1 is Lys(Ac) or (D)Lys(Ac).

[0187] In one embodiment, Xaa2 is Lys(Ac) or (D)Lys(Ac).

[0188] In one embodiment, Xaa1 is Lys(Ac) and Xaa2 is (D)Lys(Ac).

[0189] In one embodiment, Xbb1 is Glu, hGlu, or bhGlu.

[0190] In another embodiment, Xbb1 is isoAsp or Asp(OMe).

[0191] In another embodiment, Xbb1 is Gla or Glp. In a particular embodiment, Xbb1 is Glu.

[0192] In one embodiment, J is any amino acid. In another embodiment, J is absent. In another embodiment, J is Arg. In another embodiment, J is Lys. In another embodiment, J is (D)Lys.

[0193] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (sequence number 253), -Pro-Arg-Ser-Lys-Cys- (sequence number 253) 152 ), or -Pro-Arg-Ser-Lys-Sar-Cys-(array sequence number) 153 )

[0194] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (Sequence ID 253), or -Pro-Arg-Ser-Lys-Cys- (Sequence ID 253). 152 )

[0195] In one embodiment, -J-Y1-Y2- is His-(D)Phe-Arg-Trp-Cys- (Sequence ID 140) That is the case.

[0196] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Pro-Lys-Cys-, -Pro-(D)Lys-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg,-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, or -Pro-Arg-Ser-Cys- (Sequence ID 253).

[0197] In another embodiment, -J-Y1-Y2- is -(D)Lys-Cys- or -Lys-Cys-.

[0198] In another embodiment, -J-Y1-Y2- is -(D)Lys-Cys-.

[0199] In another embodiment, -J-Y1-Y2- is -Lys-Cys-.

[0200] In another embodiment, -J-Y1-Y2- is -Arg-Cys-.

[0201] In another embodiment, -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-(sequence number). 152 )

[0202] In another embodiment, -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-Lys-(sequence number)154 )

[0203] In another embodiment, -J-Y1-Y2- is -Pro-Cys-.

[0204] In another embodiment, -J-Y1-Y2- is -Cys-.

[0205] In another embodiment, -J-Y1-Y2- is -(D)Lys-Pen-.

[0206] In one embodiment, R 2 In another embodiment, R 2 It is OH.

[0207] In one embodiment, L1 is a single bond. In another embodiment, L1 is iso-Glu. In another embodiment, L1 is Ahx. In another embodiment, L1 is iso-Glu-Ahx. In another embodiment, L1 is PEG. In another embodiment, L1 is PEG-iso-Glu. In another embodiment, L1 is PEG-Ahx.

[0208] In another embodiment, L1 is iso-Glu-PEG-Ahx. In another embodiment, PEG is PEG1, PEG2, PEG3, PEG4, PEG53, or PEG11.

[0209] In one embodiment, Z is C8~C 20 Alkanic acid or C8~C 20 It is an alkanediic acid. In one embodiment, C8~C 20 Alkanes are CH3(CH2) 6-18 In one embodiment, C8~C 20 Alkanedioic acid is (CO2H)(CH2) 7-18 In one embodiment, C8~C 20 Alkanedioic acids are C8-C 20 It is also called diacid.

[0210] In another embodiment, Z is Palm.

[0211] In another embodiment, L1 is Ahx and Z is Palm.

[0212] In another embodiment, L1 is PEG11 and Z is Palm.

[0213] In another embodiment, L1 is a Dap and Z is a Palm.

[0214] In another embodiment, L1 is a dDap and Z is a Palm.

[0215] In one embodiment, 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 from 1 to 100, or 10K, 20K, or 30K.

[0216] In one embodiment, m is 1. In another embodiment, m is 2.

[0217] In one embodiment, n is 2. In another embodiment, n is 4. In another embodiment, n is 8. In another embodiment, n is 11. In another embodiment, n is 12. In another embodiment, n is 20K.

[0218] In one embodiment, PEG is 1Peg2, and 1Peg2 is -C(O)-CH2-(Peg)2-N(H)-.

[0219] In another embodiment, PEG is 2Peg2, and 2Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0220] In another embodiment, PEG is 1Peg2-1Peg2, where each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0221] In another embodiment, PEG is 1PEG2-1PEG2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-.

[0222] In another embodiment, PEG is 2Peg4, where 2Peg4 is -C(O)-CH2-CH2-(Peg)4-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-.

[0223] In another embodiment, PEG is 1Peg8, where 1Peg8 is -C(O)-CH2-(Peg)8-N(H)- or -[C(O)-CH2-(OCH2CH2)8-NH]-.

[0224] In another embodiment, PEG is 2Peg8, where 2Peg8 is -C(O)-CH2-CH2-(Peg)8-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-.

[0225] In another embodiment, PEG is 1Peg11, and 1Peg11 is -C(O)-CH2-(Peg) 11 -N(H)-, or -[C(O)-CH2-(OCH2CH2)] 11 -NH]- is

[0226] In another embodiment, PEG is 2Peg11, and 2Peg11 is -C(O)-CH2-CH2-(Peg) 11 -N(H), or -[C(O)-CH2-CH2-(OCH2CH2) 11 -NH]- is

[0227] In another embodiment, PEG is 2Peg11' or 2Peg12, where 2Peg11' or 2Peg12 is -C(O)-CH2-CH2-(Peg) 12 -N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)] 12 -NH]- is

[0228] In one embodiment, when PEG is bonded to Lys, the -C(O)- of PEG is the N of Lys. ε It will be joined to

[0229] In one embodiment, when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu.

[0230] In one embodiment, when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx.

[0231] In one embodiment, when PEG is coupled to Palm, the -N(H)- of PEG is coupled to the -C(O)- of Palm.

[0232] In one embodiment, the peptide is of formula (XXI): R 1 -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (XXI) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as described in claim 1; R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2 However, it is either NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is either Glu or does not exist.

[0233] In one embodiment, -L1Z is -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000407.tif18128. Ahx is -[C(O)-(CH2)5-NH]-

[0234] In one embodiment, -L1Z is -1PEG2_1PEG2_Dap_C18_Dioxide, -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18_diacid, During the ceremony: PEG2, PEG8, PEG4, and PEG12 are as described herein; Cn diacid is -C(O)-(CH2) n-2 It is -COOH, and n is 10, 12, 14, 16, 18, or 22.

[0235] In one embodiment, the peptide is of formula (XXII): R 1 -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7(L1Z)-J-Y1-Y2-R 2 (XXII) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as described in the claim; R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, C2~C 20 Alkenoyl, or C1~C 20 It is a cycloalkanoyl; R 2However, it is either NH2 or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is either Lys or (D)Lys.

[0236] In one embodiment, each of -L1Z is independently, -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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_Dioxide, -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18_diacid, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000408.tif18128. Ahx is -[C(O)-(CH2)5-NH]-, Cn diacid is -C(O)-(CH2) n-2 It is -COOH, and n is 10, 12, 14, 16, 18, or 22.

[0237] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_isoGlu_C n It is a diacid, and Lys(1PEG2_1PEG2_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000409.tif21148, where n is 10, 12, 14, 16, or 18.

[0238] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(1PEG2_1PEG2_isoGlu_C n (Diacid) and (D)Lys(1PEG2_1PEG2_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000410.tif21148, where n is 10, 12, 14, 16, or 18.

[0239] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG8_isoGlu_C n It is a diacid, and Lys(1PEG8_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000411.tif21148, where n is 10, 12, 14, 16, or 18.

[0240] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(1PEG8_isoGlu_C n (Diacid) and (D)Lys(1PEG8_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000412.tif21148, where n is 10, 12, 14, 16, or 18.

[0241] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_Dap_C n _Diacid) and Lys(1PEG2_1PEG2_Dap_C n (Diacid) is, The filename is TIFF2026048851000413.tif25138, where n is 10, 12, 14, 16, or 18.

[0242] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(isoGlu_C n _Diacid) and Lys(isoGlu_C n (Diacid) is, The filename is TIFF2026048851000414.tif21128, where n is 10, 12, 14, 16, or 18.

[0243] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(isoGlu_C n (Diacid) and (D)Lys(IsoGlu_C n (Diacid) is, The filename is TIFF2026048851000415.tif21128, where n is 10, 12, 14, 16, or 18.

[0244] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_isoGlu_C n It is a diacid, and Lys(PEG12 isoGlu C n (Diacid) is, The filename is TIFF2026048851000416.tif19128, where n is 10, 12, 14, 16, or 18.

[0245] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_isoGlu_C n (Diacid) and (D)Lys(PEG12_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000417.tif20128, where n is 10, 12, 14, 16, or 18.

[0246] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_isoGlu_C n It is a diacid, and Lys(PEG4_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000418.tif21137, where n is 10, 12, 14, 16, or 18.

[0247] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_isoGlu_C n (Diacid) and (D)Lys(PEG4_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000419.tif21139, where n is 10, 12, 14, 16, or 18.

[0248] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_PEG4_isoGlu_C n It is a diacid, and Lys(PEG4_PEG4_isoGlu_C n (Diacid) is, The filename is TIFF2026048851000420.tif21137, where n is 10, 12, 14, 16, or 18.

[0249] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_PEG4_isoGlu_C n (D)Lys(PEG4_PEG4_isoGlu_C) n (Diacid) is, The filename is TIFF2026048851000421.tif21137, where n is 10, 12, 14, 16, or 18.

[0250] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(isoGlu_C n _Diacid) and Lys(isoGlu_C n (Diacid) is, The filename is TIFF2026048851000422.tif24128, where n is 10, 12, 14, 16, or 18.

[0251] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(isoGlu_C n (Diacid) and (D)Lys(IsoGlu_C n (Diacid) is, The filename is TIFF2026048851000423.tif24128, where n is 10, 12, 14, 16, or 18.

[0252] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C n _Diacid) and Lys(PEG12_Ahx_C n (Diacid) is, The filename is TIFF2026048851000424.tif21130, where n is 10, 12, 14, 16, or 18.

[0253] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C n _Diacid) and Lys(PEG12_Ahx_C n (Diacid) is, The filename is TIFF2026048851000425.tif21130, where n is 10, 12, 14, 16, or 18.

[0254] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_Ahx_C n (Diacid) and (D)Lys(PEG12_Ahx_C n (Diacid) is, The filename is TIFF2026048851000426.tif21130, where n is 10, 12, 14, 16, or 18.

[0255] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_C n _Diacid) and Lys(PEG12_C n (Diacid) is, The filename is TIFF2026048851000427.tif21128, where n is 10, 12, 14, 16, or 18.

[0256] In one embodiment, Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_C n (Diacid) and (D)Lys(PEG12_C n (Diacid) is, The filename is TIFF2026048851000428.tif20128, where n is 10, 12, 14, 16, or 18.

[0257] In one embodiment, Xbb1 is Glu, (Me)Glu, (OMe)Glu, hGlu, or bhGlu.

[0258] In one embodiment, Xbb1 is isoAsp or Asp(OMe).

[0259] In one embodiment, Xbb1 is Gla or Glp.

[0260] In one embodiment, Xbb1 is Glu.

[0261] In one embodiment, Xbb1 is Glu, Glu-OMe, isoGlu, (D)Glu, or (D)isoGlu.

[0262] In one embodiment, B1 is Dpa or Phe.

[0263] In one embodiment, B1 is Dpa.

[0264] In one embodiment, B2 is Pro, Pro propanoate, Pro butanoate, bhPro, or NPC.

[0265] In one embodiment, B2 is Pro.

[0266] In one embodiment, B6 is bhPhe or Phe.

[0267] In one embodiment, B6 is bhPhe.

[0268] In one embodiment, B7 is either Glu or absent.

[0269] In one embodiment, B7 is Glu.

[0270] In one embodiment, B7 does not exist.

[0271] In one embodiment, J is (D)Lys, MeLys, or Arg.

[0272] In one embodiment, J is (D)Lys.

[0273] In one embodiment, Y1 is Cys, (D)Cys, NMeCys, aMeCys, or Pen.

[0274] In one embodiment, Y1 is Cys.

[0275] In one embodiment, R 2 It is NH2.

[0276] In one embodiment, R 2 It is OH.

[0277] In one embodiment, the present invention relates to formula (LI): R 1 -Xbb1-Xcc1-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LI) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either -NH2 or -OH; Xbb1 is isoAsp, Asp(OMe), Glu, bhGlu, bGlu, Gla, or Glp; Xcc1 is any amino acid other than Thr, and Xdd1 is any amino acid, or Xcc1 is any amino acid, and Xdd1 is any amino acid other than His; Xaa1 is B5, i) Whether B5 is nonexistent, Lys, D-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or ii) Xaa1 is B5(L1Z), B5 is Lys, D-Lys, or Lys(Ac), Xaa2 is B7, B7 is either Glu or absent; Each of B1 and B6 is independently Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-MeCys, or Pen; B4 is Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is the aminohexanoic acid moiety and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -, Peg is -OCH2CH2-, m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence number 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or none of the above, or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen, and Y2 is an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula LI optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0278] In one embodiment, Xcc1 is any amino acid other than Thr, and Xdd1 is any amino acid. In one embodiment, Xdd1 is His.

[0279] In one embodiment, the hepcidin analog is given by formula II: R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LII) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xcc1 is any amino acid other than Thr, and R 1 , R 2 Xaa1, Xbb1, B1-B4, B6, J, Y1, and Y2 are as described for formula (LI).

[0280] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab. In another embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

[0281] In one embodiment, Xcc1 is any amino acid, and Xdd1 is any amino acid other than His.

[0282] In one embodiment, Xcc1 is Thr.

[0283] In one embodiment, the hepcidin analog is given by formula III: R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LIII) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xdd1 is any amino acid other than His, and R 1 , R 2 Xaa1, Xbb1, B1-B4, B6, J, Y1, and Y2 are as described for formula (LI).

[0284] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substitute His.

[0285] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

[0286] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0287] In one embodiment, Xaa1 is B5, where B5 is non-existent, Lys, or D-Lys, and Xaa2 is B7(L1Z), where B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0288] In another embodiment, Xaa1 is B5(L1Z), where B5 is Lys or D-Lys, and Xaa2 is B7, where B7 is Glu or absent.

[0289] In one embodiment, the present invention relates to formula (LI-A1) or (LI-A2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A1), or R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LI-A2) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (LI); B7 is either Lys or D-Lys; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, then B5 is not Lys; iv) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 does not exist; v) If the peptide is a peptide dimer, the peptide dimer is a) Through the linker portion, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes the half-life extension portion.

[0290] In one embodiment, the hepcidin analog is of formula (LI-B1) or (LI-B2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LI-B1), or R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LI-B2) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (LI); i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (array array) 136 ) is either true or does not exist.

[0291] In one embodiment, B1 is F, Dpa, BIP, or bhPhe; B2 is Pro, NCP, (D)Pro, or (D)NCP; B3 is Cys, a-MeCys, or homoCys; B4 is Ile; B5 is Lys or (D)Lys; B6 is Phe, substituted Phe, bhPhe, or 2Pal; and B7 is Lys or (D)Lys.

[0292] In one embodiment, B1 is Dpa.

[0293] In one embodiment, B2 is Pro.

[0294] In one embodiment, B3 is Cys.

[0295] In one embodiment, B4 is Ile.

[0296] In one embodiment, B5 is (D)Lys.

[0297] In another embodiment, B5 is Lys(Ac).

[0298] In one embodiment, B6 is bhPhe.

[0299] In one embodiment, B7(L1Z) is -N(H)C[CH2(CH2CH2CH2) m The expression is N(H)L1Z](H)-C(O)-, where m is either 0 or 1.

[0300] In one embodiment, B7(L1Z) is -N(H)C[CH2N(H)L1Z](H)-C(O)-.

[0301] In one embodiment, B7(L1Z) is -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-.

[0302] In one embodiment, the hepcidin analog is of formula LIV or LV: R 1 -Xbb1-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LIV), or R 1 -Xbb1-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LV) Containing peptides or pharmaceutically acceptable salts thereof, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for formula (LI).

[0303] In one embodiment, Xbb1 is Glu, hGlu, or bhGlu.

[0304] In one embodiment, Xbb1 is isoAsp or Asp(OMe).

[0305] In one embodiment, Xbb1 is Glu.

[0306] In one embodiment, the hepcidin analog is of formula LVI or LVII: R 1 -Glu-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LVI), or R 1 -Glu-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LVII) Containing peptides or pharmaceutically acceptable salts thereof, During the ceremony: Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for formula (LI).

[0307] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab.

[0308] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

[0309] In one embodiment, Xcc1 is Ser, (D)Ser, or Ala.

[0310] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substitute His.

[0311] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

[0312] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (Sequence ID 253), -Pro-Arg-Ser-Lys-Cys- (Sequence ID 253) 152 ), or -Pro-Arg-Ser-Lys-Sar-Cys-(array sequence number) 153 )

[0313] In one embodiment, -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-.

[0314] In one embodiment, -J-Y1-Y2- is -(D)Lys-Cys.

[0315] In one embodiment, -J-Y1-Y2- is -Arg-Cys.

[0316] In one embodiment, L1 is a single bond.

[0317] In one embodiment, L1 is iso-Glu.

[0318] In one embodiment, L1 is Ahx.

[0319] In one embodiment, L1 is iso-Glu-Ahx.

[0320] In one embodiment, L1 is PEG.

[0321] In one embodiment, L1 is PEG-Ahx.

[0322] In one embodiment, L1 is iso-Glu-PEG-Ahx.

[0323] For a single connection, the PEG is PEG1, PEG2, PEG3, PEG4, PEG53, or PEG11.

[0324] In one embodiment, Z is Palm.

[0325] In one embodiment, R 2 It is NH2.

[0326] In one embodiment, R 2 It is OH.

[0327] In one embodiment, R 1 C1~C 20 It is Alkanoyl.

[0328] In one embodiment, R 1 It is isovaleric acid.

[0329] In one embodiment, 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 from 1 to 100, or 10K, 20K, or 30K.

[0330] In one embodiment, m is 1. In another embodiment, m is 2.

[0331] In one embodiment, n is 2. In another embodiment, n is 4. In another embodiment, n is 8. In another embodiment, n is 11. In another embodiment, n is 12. In another embodiment, n is 20K.

[0332] In one embodiment, PEG is 1Peg2, and 1Peg2 is -C(O)-CH2-(Peg)2-N(H)-.

[0333] In another embodiment, PEG is 2Peg2, and 2Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0334] In another embodiment, PEG is 1Peg2-1Peg2, where each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0335] In another embodiment, PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-.

[0336] In another embodiment, PEG is 2Peg4, where 2Peg4 is -C(O)-CH2-CH2-(Peg)4-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-.

[0337] In another embodiment, PEG is 1Peg8, where 1Peg8 is -C(O)-CH2-(Peg)8-N(H)- or -[C(O)-CH2-(OCH2CH2)8-NH]-.

[0338] In another embodiment, PEG is 2Peg8, where 2Peg8 is -C(O)-CH2-CH2-(Peg)8-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-.

[0339] In another embodiment, PEG is 1Peg11, and 1Peg11 is -C(O)-CH2-(Peg) 11 -N(H)-, or -[C(O)-CH2-(OCH2CH2)] 11 -NH]- is

[0340] In another embodiment, PEG is 2Peg11, and 2Peg11 is -C(O)-CH2-CH2-(Peg) 11 -N(H), or -[C(O)-CH2-CH2-(OCH2CH2) 11 -NH]- is

[0341] In another embodiment, PEG is 2Peg11' or 2Peg12, where 2Peg11' or 2Peg12 is -C(O)-CH2-CH2-(Peg) 12 -N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)] 12 -NH]- is

[0342] In one embodiment, when PEG is bonded to Lys, the -C(O)- of PEG is the N of Lys. ε It will be joined to

[0343] In one embodiment, when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu.

[0344] In one embodiment, when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx.

[0345] In one embodiment, when PEG is coupled to Palm, the -N(H)- of PEG is coupled to the -C(O)- of Palm.

[0346] In one embodiment, the present invention relates to formula (LVIII): R 1 -Xbb1-Xcc1-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LVIII) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R 1 However, hydrogen, C1-C6 alkyl, C6-C 12 Aryl, C6~C 12Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl; R 2 However, it is either -NH2 or -OH; Xbb1 is isoAsp, Asp(OMe), Dap, D-Arg, Glu, substituted Glu, Gly, substituted Gly, bhGlu, bGlu, Gla, or Glp; Xcc1 is any amino acid; Xdd1 is any amino acid; Xaa2 is Gly, N-substituted Gly, Lys, Tle, (D)Arg, (D)Lys, Lys(Ac), or (D)Lys(Ac); Xaa1 is Gly, N-substituted Gly, Lys, NMeLys, (D)Lys, Lys(Ac), or (D)Lys(Ac), Xaa1 is B5, i) B5 is absent, Dap, Lys, D-Lys, D-Leu, D-Ala, NMe-Lys, a-Me-Lys, homoLys, or Lys(Ac), Xaa2 is B7 or B7(L1Z), and B7 is Dap, Glu, Lys, D-Lys, homoLys, or a-Me-Lys, or ii) Xaa1 is B5(L1Z), and B5 is Dap, Lys, D-Lys, D-Leu, D-Ala, NMe-Lys, a-Me-Lys, homoLys, or Lys(Ac), and Xaa2 is B7, and B7 is either Glu or absent; B1 is Gly, substituted Gly, Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, D-Cys, a-MeCys, or Pen; B4 is F, Cha, Achc, Tle, hL, D-Arg, Gly, N-substituted Gly, (Me)Ile, Ile, Val, Leu, or NLeu; B6 is Gly, substituted Gly, Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, 2Pal, BH_Phe_4Me, Aic, Achc, Hph, hL, or Igl; L1 is absent, Dap, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, isoGlu-PEG-Ahx, 1PEG2_1PEG2_Ahx, 1PEG2_1PEG2_Dap, Dap_DIP, DMG_N_2ae, Ahx-DMG_N_2ae, or PEG-PEG-DMG_N_2ae, where [Ahx is the aminohexanoic acid moiety, DMG_N_2ae is the 2-amino-N-(carboxymethyl)-N,N-dimethylethane-1-aminium moiety, and PEG is -[C(O)-CH2-(Peg) n -N(H)] m -, or -[C(O)-CH2-CH2-(Peg) n -N(H)] m -where PEG is -OCH2CH2, m is 1, 2, or 3, and n is an integer between 1 and 100K]; Z is the half-life extension portion; J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (Sequence ID 136) 、-Pro-Arg-Ser-Lys-Sar -(Sequence ID 250) 、-Pro-Arg-Ser-Lys-Gly- (Sequence ID 251) It is either not present or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMeCys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Nal is 1-naphthylalanine, 2-Nal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; Substituting bhPhe is β-homophenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted Trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-Lb-homotryptophan, α-methyl-β-homotryptophan, or β-homotryptophan, which are substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula LVIII optionally contains one or more R 1PEGylated in B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1.

[0347] In one embodiment, (L1Z) is 1PEG2_1PEG2_Ahx_C18_diacid, 1PEG2_1PEG2_Dap_C18_diacid, 1PEG2_1PEG2_Dap_C18_diacid, 1PEG2_1PEG2_Dap_C18_diacid.

[0348] In one embodiment, B5(L1Z) is Lys_1PEG2_1PEG2_Ahx_C18_diacid, Lys_1PEG2_1PEG2_Dap_C18_diacid, NMe_Lys_1PEG2_1PEG2_Dap_C18_diacid, or meLys_1PEG2_1PEG2_Dap_C18_diacid.

[0349] In one embodiment, Xbb1 is D-Arg.

[0350] In another embodiment, Xbb1 is Dap.

[0351] In another embodiment, Xcc1 is Thr.

[0352] In another embodiment, Xdd1 is Trp_5OH, Phe_4CF3, Trp_6OMe, Phe_4CF3, Trp_6OMe, 3Pal, Bip, Tyr, Trp, or 4Pal.

[0353] In a particular embodiment, Xdd1 is Trp_5OH.

[0354] In a particular embodiment, Xdd1 is Phe_4CF3.

[0355] In a particular embodiment, Xdd1 is Trp_5OMe.

[0356] In a particular embodiment, Xdd1 is Trp_5OH.

[0357] In a particular embodiment, Xdd1 is Phe_4CF3.

[0358] In a particular embodiment, Xdd1 is Trp_6OMe.

[0359] In a particular embodiment, Xdd1 is 3Pal.

[0360] In certain embodiments, Xdd1 is Bip.

[0361] In a particular embodiment, Xdd1 is Tyr.

[0362] In a particular embodiment, Xdd1 is Trp.

[0363] In a particular embodiment, Xdd1 is 4Pal.

[0364] In another embodiment, B4 is F.

[0365] In another embodiment, B4 is Cha.

[0366] In another embodiment, B4 is Achc.

[0367] In another embodiment, B4 is Tle.

[0368] In another embodiment, B4 is hL.

[0369] In another embodiment, B4 is D-Arg.

[0370] In one embodiment, Xaa1 is NMeLys.

[0371] In one embodiment, Xaa2 is Tle.

[0372] In one embodiment, Xaa2 is D-Arg.

[0373] In one embodiment, B6 is BH_Phe_4Me, Aic, Achc, Hph, hL, or Igl.

[0374] In certain embodiments, B6 is BH_Phe_4Me.

[0375] In certain embodiments, B6 is Aic.

[0376] In certain embodiments, B6 is Achc.

[0377] In certain embodiments, B6 is Hph.

[0378] In certain embodiments, B6 is hL.

[0379] In certain embodiments, B6 is Igl.

[0380] In one embodiment, B5(L1Z) is Lys_1PEG2_1PEG2_Ahx_C18_diacid, Lys_1PEG2_1PEG2_Dap_C18_diacid, NMe_Lys_1PEG2_1PEG2_Dap_C18_diacid, or meLys_1PEG2_1PEG2_Dap_C18_diacid.

[0381] In one embodiment, B5(L1Z) is Lys_1PEG2_1PEG2_Ahx_C18_diacid.

[0382] In one embodiment, B5(L1Z) is Lys_1PEG2_1PEG2_Dap_C18_diacid.

[0383] In one embodiment, B5(L1Z) is NMe_Lys_1PEG2_1PEG2_Dap_C18_diacid.

[0384] In one embodiment, B5(L1Z) is meLys_1PEG2_1PEG2_Dap_C18_diacid.

[0385] In one embodiment, B7(L1Z) is Dap cyclohexanoic acid, Dap 15 pentanodic acid, Dap imidazole acetate, Dap butanoic acid 3OH, Dap DIP CH2CO2H, Dap phenylacetic acid 4F, Dap Ahx, or Dap IVA.

[0386] In one embodiment, B7(L1Z) is Dap_cyclohexanoic acid.

[0387] In one embodiment, B7(L1Z) is Dap_1_5_pentanediic acid.

[0388] In one embodiment, B7(L1Z) is Dap-imidazole acetate.

[0389] In one embodiment, B7(L1Z) is Dap_butanoic acid_3OH.

[0390] In one embodiment, B7(L1Z) is Dap_DIP_CH2CO2H.

[0391] In one embodiment, B7(L1Z) is Dap_phenylacetic acid_4F.

[0392] In one embodiment, B7(L1Z) is Dap_Ahx.

[0393] In one embodiment, B7(L1Z) is Dap_IVA.

[0394] In one embodiment, Xcc1 is any amino acid. In one embodiment, Xcc1 is Thr.

[0395] In one embodiment, Xdd1 is any amino acid. In one embodiment, Xdd1 is His.

[0396] In certain embodiments, -L1Z is independently one of the following: -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -PEG12_Ahx_Palm, -PEG12_DEKHKS_Palm, -PEG12 iso-Glu 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_Dioxide, -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 iso-Glu C18 diacid, -Iso-Glu C18 diacid, -PEG12_Ahx_C18_Diacid, -DMG_N_2ae, -Ahx-DMG_N_2ae, -1PEG2-1PEG2-DMG_N_2ae, -PEG12_C16_Diacid, -PEG12_C18_diacid, -1PEG2_1PEG2_1PEG2_C18_Diacid, -1PEG2_1PEG2_1PEG2_isoGlu_C18_diacid, -PEG12 iso-Glu C18 diacid, -PEG4 iso-Glu C18 diacid, or -PEG4_PEG4_isoGlu_C18 diacid, During the ceremony: 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-, Ado is -[C(O)-(CH2) 11 -NH]- Cn acid is -C(O)(CH2) n-2 -CH3, and C18 acid is -C(O)-(CH2) 16 -Me, Palm is -C(O)-(CH2) 14 -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, The filename is TIFF2026048851000429.tif18128. Ahx is -[C(O)-(CH2)5-NH]-, Cn diacids are -C(O)-(CH2) n-2 It is -COOH, and n is 10, 12, 14, 16, 18, or 22. DMG_N_2ae is N,N-dimethyl-N-(2-(methylamino)ethyl)-2-oxopropane-1-aminium TIFF2026048851000430.tif16128, or This is Ahx_DMG_N_2ae_Palm.

[0397] In one embodiment, the hepcidin analog is given by formula LIX: R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LIX) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xcc1 is any amino acid other than Thr, and R 1 , R 2 Xaa1, Xbb1, B1-B4, B6, J, Y1, and Y2 are as described for formula (LVIII).

[0398] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab. In another embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

[0399] In one embodiment, Xcc1 is any amino acid, and Xdd1 is any amino acid other than His.

[0400] In one embodiment, Xcc1 is Thr.

[0401] In one embodiment, the hepcidin analog is given by formula III: R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R 2 (LX) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xdd1 is any amino acid other than His, and R 1 , R 2 Xaa1, Xbb1, B1-B4, B6, J, Y1, and Y2 are as described for formula (LVIII).

[0402] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substitute His.

[0403] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

[0404] In one embodiment, the half-life extension portion is C 10 ~C 21 It is Alkanoyl.

[0405] In one embodiment, Xaa1 is B5, where B5 is non-existent, Lys, or D-Lys, and Xaa2 is B7(L1Z), where B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

[0406] In another embodiment, Xaa1 is B5(L1Z), where B5 is Lys or D-Lys, and Xaa2 is B7, where B7 is Glu or absent.

[0407] In one embodiment, the present invention relates to formula (LVIII-A1) or (LVIII-A2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LVIII-A1), or R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R 2 (LVIII-A2) A hepcidin analog containing the peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (LVIII); B7 is either Lys or D-Lys; Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, then B5 is not Lys; iv) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 does not exist; v) If the peptide is a peptide dimer, the peptide dimer is a) Through the linker portion, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes the half-life extension portion.

[0408] In one embodiment, the hepcidin analog is of formula (LVIII-B1) or (LVIII-B2): R 1 -Xbb1-Xcc1-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LVIII-B1), or R 1-Xbb1-Thr-Xdd1-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R 2 (LVIII-B2) The peptides contained therein, or their pharmaceutically acceptable salts or solvates, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 B1-B6, L1, Z, J, Y1, and Y2 are as described for formula (LVIII); Here: i) The peptide of formula I optionally contains one or more R 1 PEGylated in B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (array array) 136 ) is either true or does not exist.

[0409] In one embodiment, B1 is F, Dpa, BIP, or bhPhe; B2 is Pro, NCP, (D)Pro, or (D)NCP; B3 is Cys, a-MeCys, or homoCys; B4 is Ile; B5 is Lys or (D)Lys; B6 is Phe, substituted Phe, bhPhe, or 2Pal; and B7 is Lys or (D)Lys.

[0410] In one embodiment, B1 is Dpa.

[0411] In one embodiment, B2 is Pro.

[0412] In one embodiment, B3 is Cys.

[0413] In one embodiment, B4 is Ile.

[0414] In one embodiment, B5 is (D)Lys.

[0415] In another embodiment, B5 is Lys(Ac).

[0416] In one embodiment, B6 is bhPhe.

[0417] In one embodiment, B7(L1Z) is -N(H)C[CH2(CH2CH2CH2) m The expression is N(H)L1Z](H)-C(O)-, where m is either 0 or 1.

[0418] In one embodiment, B7(L1Z) is -N(H)C[CH2N(H)L1Z](H)-C(O)-.

[0419] In one embodiment, B7(L1Z) is -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-.

[0420] In one embodiment, the hepcidin analog is of formula LXI or LXII: R 1 -Xbb1-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LXI), or R 1 -Xbb1-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LXII) Containing peptides or pharmaceutically acceptable salts thereof, During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described for equation (LVIII).

[0421] In one embodiment, Xbb1 is Glu, hGlu, or bhGlu.

[0422] In one embodiment, Xbb1 is isoAsp or Asp(OMe).

[0423] In one embodiment, Xbb1 is Glu.

[0424] In one embodiment, the hepcidin analog is of formula LXIII or LXIV: R 1 -Glu-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LXIII), or R 1 -Glu-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (LXIV) Containing peptides or pharmaceutically acceptable salts thereof, During the ceremony: Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as shown in formula (LVIII).

[0425] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab.

[0426] In one embodiment, Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

[0427] In one embodiment, Xcc1 is Ser, (D)Ser, or Ala.

[0428] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substitute His.

[0429] In one embodiment, Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

[0430] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (Sequence ID 253), -Pro-Arg-Ser-Lys-Cys- (Sequence ID 253) 152 ), or -Pro-Arg-Ser-Lys-Sar-Cys-(array sequence number) 153 )

[0431] In one embodiment, -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-.

[0432] In one embodiment, -J-Y1-Y2- is -(D)Lys-Cys.

[0433] In one embodiment, -J-Y1-Y2- is -Arg-Cys.

[0434] In one embodiment, L1 is a single bond.

[0435] In one embodiment, L1 is iso-Glu.

[0436] In one embodiment, L1 is Ahx.

[0437] In one embodiment, L1 is iso-Glu-Ahx.

[0438] In one embodiment, L1 is PEG.

[0439] In one embodiment, L1 is PEG-Ahx.

[0440] In one embodiment, L1 is iso-Glu-PEG-Ahx.

[0441] For a single connection, the PEG is PEG1, PEG2, PEG3, PEG4, PEG53, or PEG11.

[0442] In one embodiment, Z is Palm.

[0443] In one embodiment, R 2 It is NH2.

[0444] In one embodiment, R 2 It is OH.

[0445] In one embodiment, R 1 C1~C 20 It is Alkanoyl.

[0446] In one embodiment, R 1 It is isovaleric acid.

[0447] In one embodiment, 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 from 1 to 100, or 10K, 20K, or 30K.

[0448] In one embodiment, m is 1. In another embodiment, m is 2.

[0449] In one embodiment, n is 2. In another embodiment, n is 4. In another embodiment, n is 8. In another embodiment, n is 11. In another embodiment, n is 12. In another embodiment, n is 20K.

[0450] In one embodiment, PEG is 1Peg2, and 1Peg2 is -C(O)-CH2-(Peg)2-N(H)-.

[0451] In another embodiment, PEG is 2Peg2, and 2Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0452] In another embodiment, PEG is 1Peg2-1Peg2, where each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-.

[0453] In another embodiment, PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-.

[0454] In another embodiment, PEG is 2Peg4, where 2Peg4 is -C(O)-CH2-CH2-(Peg)4-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-.

[0455] In another embodiment, PEG is 1Peg8, where 1Peg8 is -C(O)-CH2-(Peg)8-N(H)- or -[C(O)-CH2-(OCH2CH2)8-NH]-.

[0456] In another embodiment, PEG is 2Peg8, where 2Peg8 is -C(O)-CH2-CH2-(Peg)8-N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-.

[0457] In another embodiment, PEG is 1Peg11, and 1Peg11 is -C(O)-CH2-(Peg) 11 -N(H)-, or -[C(O)-CH2-(OCH2CH2)] 11 -NH]- is

[0458] In another embodiment, PEG is 2Peg11, and 2Peg11 is -C(O)-CH2-CH2-(Peg) 11 -N(H), or -[C(O)-CH2-CH2-(OCH2CH2) 11 -NH]- is

[0459] In another embodiment, PEG is 2Peg11' or 2Peg12, where 2Peg11' or 2Peg12 is -C(O)-CH2-CH2-(Peg) 12 -N(H)- or -[C(O)-CH2-CH2-(OCH2CH2)] 12 -NH]- is

[0460] In one embodiment, when PEG is bonded to Lys, the -C(O)- of PEG is the N of Lys. ε It will be joined to

[0461] In one embodiment, when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu.

[0462] In one embodiment, when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx.

[0463] In one embodiment, when PEG is coupled to Palm, the -N(H)- of PEG is coupled to the -C(O)- of Palm.

[0464] In one embodiment, the hepcidin analog comprises or consists of a peptide, the peptide being one of the peptides or dimers thereof listed in Table 2, and the peptide being cyclized via a disulfide bond between two Cys. In a particular embodiment, the present invention comprises a polypeptide comprising the amino acid sequences shown in Table 2, or any amino acid sequence having at least 85%, at least 90%, at least 92%, at least 94%, or at least 95% identity with any of these amino acid sequences.

[0465] In one embodiment, the hepcidin analog comprises or consists of one of the peptides listed in Table 2, the peptide being cyclized via a disulfide bond between two Cys, and * indicates that Peg11 is Peg11-OMe.

[0466] In one embodiment, R 1 These are hydrogen, C1-C6 alkyl, and C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl, and R 2 It is either -NH2 or -OH.

[0467] In one embodiment, each of B1 and B6 is independent of the other. i) Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, or D-Phe, ii) 2-Nal, 1-Nal, D-1-Nal, D-2-Nal, 3,3-diphenylGly, Tic, Bip, Trp, bhTrp, hPhe, or Tyr(Me), iii) Substitutions are Phe, bhPhe, Trp, or bhTrp.

[0468] In one embodiment, B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, or Pen; B4 is Ile, Val, Leu, or NLeu; B5 is Lys, D-Lys, Orn, homoser, Gln, Lys(Ac), Ile, Abu, Leu, or Nleu; and B7 is a lower or higher homolog of Lys.

[0469] In one embodiment, L1 is absent or is isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx, where Ahx is the aminohexanoic acid portion and L1 is the N of B7 εIt is bonded to Z, and Z is the half-life extension portion.

[0470] In one embodiment, J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (array array). 136) Y1 is either -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or absent, Y1 is Cys, homocys, or Pen, and Y2 is either an amino acid or absent.

[0471] In one embodiment, R 1 These are hydrogen, C1-C6 alkyl, and C6-C 12 Aryl, C6~C 12 Aryl-C1~C6 alkyl, C1~C 20 Alkanoyl, or C1-C 20 It is a cycloalkanoyl, and R 2 It is either -NH2 or -OH.

[0472] In one embodiment, each of B1 and B6 is independently Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal.

[0473] In one embodiment, B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homoCys, or Pen; B4 is Ile, Val, Leu, or NLeu; B5 is non-existent, Lys, or D-Lys; and B7 is a lower or higher homolog of Lys, a-MeLys, or D-Lys.

[0474] In one embodiment, L1 is either absent or is isoGlu, PEG, Ahx, isoGlu-PEG, PEG-isoGlu, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx; Ahx is the aminohexanoic acid moiety, and L1 is the N of B7. εIt is bonded to, where Z is the half-life extension part, and J is Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO: Array Number) 136 ), -Pro-Arg-Ser-Lys-Sar-(SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251), or none thereof, or J is any amino acid, Y1 is Cys, homocys, NMeCys, aMeCys, or Pen, and Y2 is an amino acid or none thereof.

[0475] In certain embodiments, B5 is D-Lys.

[0476] In one embodiment, R 1 is hydrogen, or C1~C 20 It is Alkanoyl.

[0477] In another embodiment, R 1 R is hydrogen, isovaleric acid, isobutyric acid, or acetyl. In certain embodiments, R 1 It is isovaleric acid.

[0478] In one embodiment, B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC.

[0479] In one embodiment, B3 is Cys. In another embodiment, B3 is homocystic Cys.

[0480] In one embodiment, B4 is Ile.

[0481] In one embodiment, B5 does not exist.

[0482] In another embodiment, B5 is Lys or D-Lys.

[0483] In another embodiment, the peptide is cyclized via a disulfide bond between B3 and Y1.

[0484] In one embodiment, Y1 is Cys or homocys.

[0485] In one embodiment, the half-life extension portion is C 14 ~C 20 It is Alkanoyl.

[0486] In one embodiment, B7 is a lower homolog of Lys. In another embodiment, B7 is a higher homolog of Lys. In a further embodiment, B7 is homoLys, a-MeLys, or abu. In a particular embodiment, B7 is Lys or D-Lys.

[0487] In another embodiment, B7 is Dapa.

[0488] In another embodiment, B2 is Pro or NPC, B3 is Cys, B4 is Ile, and B6 is Phe, bhPhe, or 2Pal.

[0489] In one embodiment, a lower homolog of Lys is 2,3-diaminopropanoic acid or 2,4-diaminobutyric acid. In another embodiment, a lower homolog of Lys is L-2,3-diaminopropanoic acid. In yet another embodiment, a lower homolog of Lys is D-2,3-diaminopropanoic acid. In yet another embodiment, a lower homolog of Lys is L-2,4-diaminobutyric acid. In yet another embodiment, a lower homolog of Lys is D-2,4-diaminobutyric acid.

[0490] In one embodiment, a higher homolog of Lys is homoLys or L-2,6-diaminohexanoic acid. In another embodiment, a higher homolog of Lys is D-homoLys or D-2,6-diaminohexanoic acid.

[0491] In one embodiment, B2 is Pro, D-Pro, or bhPro. In a particular embodiment, B2 is Pro.

[0492] In one embodiment, B3 is Cys. In another embodiment, B3 is Pen. In yet another embodiment, B3 is homocystic.

[0493] In one embodiment, the peptide is of formula Xa, Xb, Xc, or Xd: R 1 -Xbb1-Xcc1-His-Dpa-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xa) R 1 -Xbb1-Xcc1-His-Dpa-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xb) R 1 -Xbb1-Thr-Xdd1-Dpa-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xc) R 1 -Xbb1-Thr-Xdd1-Dpa-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)-J-Y1-Y2-R 2 (Xd) It is due to, or a pharmaceutically acceptable salt thereof. During the ceremony: Xbb1, Xcc1, Xdd1, R 1 , R 2 L1, Z, J, Y1, and Y2 are as described in equation (I).

[0494] In one embodiment, with respect to the peptide of the present invention, the Pro in -Asp-Thr-His-B1-Pro-Cys-Ile-B5-B6- is replaced with dPro or Npc.

[0495] In certain embodiments, with respect to the peptide of the present invention, the peptide is cyclized via a disulfide bond between two Cys molecules.

[0496] In one embodiment, with respect to the peptide of the present invention, -N(H)C[CH2N(H)L1Z](H)-C(O)- is an L-amino acid. In another embodiment, with respect to the peptide of the present invention, -N(H)C[CH2N(H)L1Z](H)-C(O)- is a D-amino acid.

[0497] In one embodiment, with respect to the peptide of the present invention, -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)- is an L-amino acid. In another embodiment, with respect to the peptide of the present invention, -N(H)C[CH2CH2CH2CH2N(H)L1Z](H)-C(O)- is a D-amino acid.

[0498] In one embodiment, Xbb1 is Glu, hGlu, or bhGlu.

[0499] In a particular embodiment, Xbb1 is Glu.

[0500] In one embodiment, J is any amino acid. In another embodiment, J is absent. In another embodiment, J is Arg. In another embodiment, J is Lys. In another embodiment, J is (D)Lys.

[0501] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (sequence number 253), -Pro-Arg-Ser-Lys-Cys- (sequence number 253) 152 ), or -Pro-Arg-Ser-Lys-Sar-Cys-(array sequence number) 153 )

[0502] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (Sequence ID 253), or -Pro-Arg-Ser-Lys-Cys- (Sequence ID 253). 152 )

[0503] In one embodiment, -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Pro-Lys-Cys-, -Pro-(D)Lys-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg, -Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, or -Pro-Arg-Ser-Cys- (Sequence ID 253).

[0504] In another embodiment, -J-Y1-Y2- is -(D)Lys-Cys- or -Lys-Cys-.

[0505] In another embodiment, -J-Y1-Y2- is -(D)Lys-Cys-.

[0506] In another embodiment, -J-Y1-Y2- is -Lys-Cys-.

[0507] In another embodiment, -J-Y1-Y2- is -Arg-Cys-.

[0508] In another embodiment, -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-(sequence number). 152 )

[0509] In another embodiment, -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-Lys-(sequence number) 154 )

[0510] In another embodiment, -J-Y1-Y2- is -Pro-Cys-.

[0511] In another embodiment, -J-Y1-Y2- is -Cys-.

[0512] In another embodiment, -J-Y1-Y2- is -(D)Lys-Pen-.

[0513] In certain embodiments, Xcc1 is a substitution Thr, Ser, (D)Ser, or Ala. In more specific embodiments, Xcc1 is Ser, (D)Ser, or Ala.

[0514] In certain embodiments, Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substitute His. In more specific embodiments, Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

[0515] In one embodiment, R 2 In another embodiment, R 2 It is OH.

[0516] In one embodiment, L1 is a single bond. In another embodiment, L1 is iso-Glu. In another embodiment, L1 is Ahx. In another embodiment, L1 is iso-Glu-Ahx. In another embodiment, L1 is PEG. In another embodiment, L1 is PEG-iso-Glu. In another embodiment, L1 is PEG-Ahx.

[0517] In another embodiment, L1 is iso-Glu-PEG-Ahx. In another embodiment, PEG is PEG1, PEG2, PEG3, PEG4, PEG53, or PEG11. In another embodiment, Z is Palm.

[0518] In another embodiment, L1 is Ahx and Z is Palm.

[0519] In another embodiment, L1 is PEG11 and Z is Palm.

[0520] In another embodiment, L1 is a Dap and Z is a Palm.

[0521] In another embodiment, L1 is a dDap and Z is a Palm.

[0522] In certain embodiments of peptide analogs having any of the various formulas shown herein, R 1 The selected amides are methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[0523] In certain embodiments, the linker between the peptide and the half-life extension portion is PEG11, Ahx, or any other as described herein.

[0524] In certain embodiments, the half-life extension portion is Palm.

[0525] In one embodiment, the peptide is one of the peptides listed in Tables 2A to 2B, and the peptide is cyclized via a disulfide bond between two Cy atoms.

[0526] In one embodiment, the peptide comprises or consists of one of the peptides listed in Tables 2A to 2B, the peptide is cyclized via a disulfide bond between two Cys molecules, and * indicates that Peg11 is Peg11-OMe.

[0527] In one embodiment, the peptide is as follows: Compound ID number 12 TIFF2026048851000431.tif27151 Compound ID number 19 TIFF2026048851000432.tif117151 Compound ID number 107 TIFF2026048851000433.tif41151 Compound ID number 113 TIFF2026048851000434.tif22151 Compound ID number 256 TIFF2026048851000435.tif27151 Compound ID number 257 TIFF2026048851000436.tif27151 Compound ID number 280 TIFF2026048851000437.tif53151 Compound ID number 281 TIFF2026048851000438.tif62151

[0528] In certain embodiments, the peptide is Compound ID number 255 TIFF2026048851000439.tif27151 or, Compound ID number 280 The filename is TIFF2026048851000440.tif53151.

[0529] In one embodiment, X3 is 1-MeHis or His(1-Me).

[0530] In one embodiment, B2 is Lys. In one embodiment, B2 is Lys substituted with acrylamide.

[0531] In one embodiment, B3 is a-MeCys.

[0532] In one embodiment, B4 is Me-substituted Ile.

[0533] In one embodiment, B5 is a-MeLys.

[0534] In one embodiment, B5(L1Z) is Lys substituted with acrylamide.

[0535] In one embodiment, B5(L1Z) is Lys replaced with 1PEG2_1PEG2_Ahx_C18_OMe.

[0536] In one embodiment, B6 is Phe substituted with Me.

[0537] In one embodiment, B7(L1Z) is aMeLys replaced with Ahx_Palm.

[0538] In one embodiment, B7(L1Z) is Lys replaced with PEG30K or PEG40K.

[0539] In certain embodiments of peptide analogs having any of the various formulas shown herein, R 1 The selected amides are methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[0540] In certain embodiments, the linker between the peptide and the half-life extension portion is PEG11, Ahx, or any other as described herein.

[0541] In certain embodiments, the half-life extension portion is Palm.

[0542] In certain embodiments, the present invention includes a polypeptide comprising an amino acid sequence shown in Tables 2A to 2B (with or without the indicated linker and half-life extension portions), or any amino acid sequence having at least 85%, at least 90%, at least 92%, at least 94%, or at least 95% identity with any of these amino acid sequences.

[0543] In certain embodiments, the present invention provides a cyclized form of any one of the hepcidine analogs disclosed herein or listed in either Table 2A or Table 2B, comprising a disulfide bond between two Cys and / or Pen residues. The conjugated half-life extension portion and the amino acid residue to which it is conjugated are indicated by parentheses and square brackets, respectively. Compound ID numbers are indicated by "Compd ID," and reference compounds are indicated by "Ref.Compd."

[0544] (Table 2A) Exemplary monomeric hepcidin analogs JPEG2026048851000441.jpg167159TIFF2026048851000442.tif222151TIFF2026048851000443.t if220151TIFF2026048851000444.tif226151TIFF2026048851000445.tif219151TIFF2026048851 000446.tif229151TIFF2026048851000447.tif229151TIFF2026048851000448.tif230151TIFF20 26048851000449.tif220151TIFF2026048851000450.tif220151TIFF2026048851000451.tif37153

[0545] (Table 2B) Exemplary monomeric hepcidin analogs TIFF2026048851000452.tif180152TIFF2026048851000453.tif228151TIFF2026048851000454.tif230151TIFF2026048851000455.tif223151 TIFF2026048851000456.tif229151TIFF2026048851000457.tif223151TIFF2026048851000458.tif228151TIFF2026048851000459.tif112153

[0546] In certain embodiments, the present invention includes a polypeptide comprising an amino acid sequence shown in Table 2C (with or without the indicated linker moiety and half-life extension moiety), or any amino acid sequence having at least 85%, at least 90%, at least 92%, at least 94%, or at least 95% identity with any of these amino acid sequences. In certain embodiments, the present invention provides a cyclization form of any one of the hepcidine analogs disclosed herein or listed in Table 1, comprising a disulfide bond between two Cys and / or Pen residues. The conjugated half-life extension moiety and the amino acid residue to which it is conjugated are indicated by parentheses and square brackets, respectively. Compound ID numbers are indicated by "Compd ID," and reference compounds are indicated by "Ref.Compd.". The FPN IC determined from this data 50 The values ​​are shown in Table 1 as follows: **** = 1nM to 30nM, *** = 31nM to 100nM, ** = 101nM to 500nM, * = 500nM. The TD47D IC was determined from this data. 50 The values ​​are shown in Table 1 as follows: **** = 1nM to 10nM, *** = 11nM to 100nM, ** = 101nM to 500nM, * = 500nM. If not shown, the data has not yet been determined.

[0547] (Table 2C) Exemplary monomeric hepcidin analogs JPEG2026048851000460.jpg236159JPEG2026048851000461.jpg190159

[0548] In certain embodiments, the present invention includes a polypeptide comprising an amino acid sequence shown in Table 2D (with or without the shown linker moiety and half-life extension moiety), or any amino acid sequence having at least 85%, at least 90%, at least 92%, at least 94%, or at least 95% identity with any of these amino acid sequences.

[0549] (Table 2D) Exemplary monomeric hepcidin analogs TIFF2026048851000462.tif217154TIFF2026048851000463.tif229151TIFF2026048851000464.t if229151TIFF2026048851000465.tif229151TIFF2026048851000466.tif225151TIFF20260488510 00467.tif224151TIFF2026048851000468.tif230151TIFF2026048851000469.tif220151TIFF202 6048851000470.tif230151TIFF2026048851000471.tif225151TIFF2026048851000472.tif213153

[0550] In certain embodiments, the present invention includes a hepcidin analog having the structure shown below or comprising an amino acid sequence, Isovaleric acid-ETHFPCI-(D)Lys-F-Lys[2Peg11'-Palm]-KC-NH2 (Sequence ID 1) , Isovaleric acid-ETH-DIP-PCI-(D)Lys-DIP-Lys[2Peg11'-Palm]-(D)Lys-C-NH2 (Sequence 2) , Isovaleric acid-ETH-DIP-PCI-(D)Lys-bhPhe-Lys[2Peg11'-Palm]-(D)Lys-C-NH2 (Sequence ID 3) , Isovaleric acid-ETH-DIP-PCI-(D)Lys-bhPhe-Lys[2Peg11'-Palm]-C-(D)Lys-NH2 (Sequence No. 4) , Isovaleric acid-isoAsp-THFPCIK(isoGlu-Palm)-FEPRSKGCK-NH2 (Sequence ID 161) , Isovaleric acid-ETH-[Dpa]-[Npc]-CI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence ID 5) , Iso-glycine-ETH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence ID 6) , Iso-glycine-bhGlu-TH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence ID 7) , Iso-glycine-bE-TH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence 8) , Iso-glycine-Asp(OMe)-TH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence ID 9) , Iso-glycine-Gla-TH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-(D)Lys-C-NH2 (Sequence ID 10) , Iso-glycine-ETH-[Dpa]-PCI-(D)Lys-bhPhe-[Lys(Ahx-Palm)]-RC-NH2 (Sequence ID 11) , Iso-glycine-ETH-[Dpa]-PCI-Lys[1Peg2-1Peg2-Ahx-Palm]-bhPhe-(D)Lys-C-NH2 (Sequence ID 12) , Iso-glyoxalic acid-ETH-[Dpa]-PCI-Lys[1Peg2-1Peg2-Ahx-Palm]-bhPhe-RC-NH2 (Sequence ID 13) , イソYoshioxalic acid-ETH-[Dpa]-PCI-Lys[1Peg2-1Peg2-イソGlu-Palm]-bhPhe-RC-NH2 (Sequence ID 14) , Iso-glycine-ETH-[Dpa]-PCI-(D)Lys-bhPhe-Lys[1Peg2-1Peg2-Ahx-Palm]-RC-NH2 (Sequence ID 15) , Isovaleric acid-ETH-[Dpa]-PCI-(D)Lys-bhPhe-Lys[1Peg2-1Peg2-isoGlu-Palm]-RC-NH2 (Sequence ID 16) , Isovaleric acid-ETH-[Dpa]-PCI-[Lys(Ahx-Palm)]-bhPhe-RC-NH2 (Sequence ID 17) , Isovaleric acid-ETH-[Dpa]-PCI-(D)Lys[2PEG11']-bhPhe-[Lys(Ahx-Palm)]-RC-NH2 (Sequence No. 18) , Isovaleric acid-ETH-[Dpa]-PCI-(D)Lys[2PEG11']-bhPhe-[Lys(Ahx-Palm)]-(D)Lys[2Peg11_OMe]-C-NH2 (Sequence ID 19) , Isovaleric acid-Glp-THFPCIK (isoGlu-Palm)-FEPRSKGCK-NH2 (Sequence ID 20) , Isovaleric acid-ETH-[Dpa]-PCI-[Lys(Ahx-Palm)]-2Pal-C-NH2 (Sequence ID 21) , Isovaleric acid-ETH-[Dpa]-PCI-[Lys(Ahx-Palm)]-2Pal-RC-NH2 (Sequence ID 22) , Isovaleric acid-ETH-[Dpa]-PCI-Lys[1Peg2-1Peg2-Ahx-Palm]-2Pal-RC-NH2 (Sequence No. 23) , or Isovaleric acid-ETH-[Dpa]-PCI-Lys[1Peg2-1Peg2-isoGlu-Palm]-2Pal-RC-NH2 (Sequence ID 24) The peptide is cyclized via a disulfide bond between two Cys molecules.

[0551] In certain embodiments, the present invention includes a hepcidin analog having the structure shown below or comprising an amino acid sequence, Iso-glycine-ET-[3Pal]-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 601) , Iso-glycine-ET-[2Pal]-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 602) , Iso-glycine-ET-[3Quin]-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 603) , Iso-glycine-ET-Dab-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 604) , Iso-glycine-ET-Dap-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 605) , Iso-glycine-ET-Orn-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 606) , Iso-glycine-ESH-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 607) , Yoshiki oxalic acid-E-Dap-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 608) , Yoshiki oxalic acid-E-[(D)Asp]-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-R-[Cys]-NH2 (Sequence ID 609) , Yoshiki oxalic acid-ESH-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 610) , Iso-glycine-E-[(D)Ser]-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 611) , Yoshiki oxalic acid-E-Dab-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(2Peg11'_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 612) , Yoshiki oxalic acid-ESH-[Dpa]-P-[Cys]-I-[(D)Lys]-[a-MePhe]-[Lys(2Peg11'_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 613) , Iso-glycine-EAH-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 614) , Iso-glycine-ETA-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 615) , Iso-glycine-ETA-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 616) , Iso-glycine-E-[Me_Thr]-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 617) , Iso-glycine-ET-[MeHis]-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 618) , Isovaleric acid-ELH-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 619) , Isovaleric acid-ETL-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 620) , or Isovaleric acid-E-Hyp-H-[Dpa]-P-[Cys]-I-[(D)Lys]-[bhPhe]-[Lys(Ahx_Palm)]-[(D)Lys]-[Cys]-NH2 (Sequence ID 621) The peptide is cyclized via a disulfide bond between two Cys molecules.

[0552] In certain embodiments, the present invention comprises a hepcidin peptide having the structure shown below or comprising an amino acid sequence.

[0553] (Table 2E) Exemplary peptides of the present invention TIFF2026048851000473.tif145153TIFF2026048851000474.tif187151TIFF2026048851000475.tif201151 TIFF2026048851000476.tif203151TIFF2026048851000477.tif226151TIFF2026048851000478.tif184151 TIFF2026048851000479.tif214151TIFF2026048851000480.tif206151TIFF2026048851000481.tif209151 TIFF2026048851000482.tif209151TIFF2026048851000483.tif219151TIFF2026048851000484.tif193151 TIFF2026048851000485.tif210151TIFF2026048851000486.tif170151TIFF2026048851000487.tif20115 1TIFF2026048851000488.tif201151TIFF2026048851000489.tif187151TIFF2026048851000490.tif94153

[0554] In certain embodiments, the present invention provides a peptide or a peptide dimer thereof, the peptide comprising or consisting of any one of the peptides disclosed herein or listed in any of Tables 2A-2E and 3. In one embodiment, the peptide comprises a disulfide bond between two Cys, between Cys and N-MeCys, or between Cys and Pen residues. In certain embodiments, the peptide is any one of the peptides having an FPN activity of <100 nM. In another particular embodiment, the peptide is any one of the peptides having an FPN activity of <50 nM. In yet another particular embodiment, the peptide is any one of the peptides having an FPN activity of <20 nM. In yet another particular embodiment, the peptide is any one of the peptides having an FPN activity of <10 nM. In a more particular embodiment, the peptide is any one of the peptides having an FPN activity of <5 nM.

[0555] In certain embodiments, the peptide is selected from the group of peptides listed in Tables 2A-2E, and has an SIF half-life of >24 hours.

[0556] Peptide analog conjugates In certain embodiments, the hepcidin analogs of the present invention, including both monomeric and dimeric forms, contain one or more conjugated chemical substituents, such as lipophilic substituents and polymeric substituents, collectively referred herein as half-life extension portions. While we do not wish to be bound by any particular theory, it is thought that the lipophilic substituents bind to albumin in the bloodstream, thereby preventing the hepcidin analog from enzymatic degradation and thus increasing its half-life. Furthermore, it is hypothesized that the polymeric substituents may increase the half-life, reduce clearance in the bloodstream, and, in some cases, enhance epithelial permeability and retention in the lamina propria. Those skilled in the art will be familiar with preferred techniques for preparing the compounds used in the context of the present invention. For non-limiting examples of suitable chemistry, see, for example, 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).

[0557] In one embodiment, the side chain of one or more amino acid residues (e.g., Lys residues) in the hepcidin analog of the present invention is further conjugated (e.g., covalently bonded) to a lipophilic substituent or another half-life extension moiety. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain, or it may be conjugated to the amino acid side chain via one or more spacer or linker moieties. The spacer or linker moiety, if present, may provide a gap between the hepcidin analog and the lipophilic substituent.

[0558] In certain embodiments, the lipophilic substituent or half-life extender comprises a hydrocarbon chain having 4 to 30 carbon atoms, for example, at least 8 or 12 carbon atoms, preferably 24 or fewer carbon atoms, or 20 or fewer carbon atoms. The hydrocarbon chain may be linear or branched, and may be saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a portion that forms part of the bond to the amino acid side chain or 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 therefore the hydrocarbon chain may form part of an alkanoyl group, for example, palmitoyl, caproyl, lauroyl, myristoyl, or stearoyl.

[0559] Lipophilic substituents can be conjugated to any amino acid side chain in the hepcidine analog of the present invention. In certain embodiments, the amino acid side chain includes a carboxy, hydroxyl, thiol, amide, or amine group for forming an ester, sulfonyl ester, thioester, amide, or sulfonamide with a spacer or lipophilic substituent. For example, the lipophilic substituent can 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. The amino acid represented as Lys in any of the formulas provided herein can be replaced, for example, by Dbu, Dpr, or Orn to which the lipophilic substituent is added.

[0560] In further embodiments of the present invention, or, in addition, the side chains of one or more amino acid residues in the hepcidin analog of the present invention may be conjugated to a polymer moiety or other half-life extension moiety to increase solubility and / or half-life and / or bioavailability, for example, in vivo (e.g., in plasma). Such modifications are also known to reduce the clearance of therapeutic proteins and peptides (e.g., renal clearance).

[0561] As used herein, "polyethylene glycol" or "PEG" refers to the general formula H-(O-CH2-CH2) nPEG is a polyether compound of -OH. Depending on its molecular weight, PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), and as used herein, PEO, PEE, or POG refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG tends to refer to oligomers and polymers with molecular weights less than 20,000 g / mol, PEO to polymers with molecular weights greater than 20,000 g / mol, and POE to polymers with any molecular weight. Depending on their molecular weight, PEG and PEO are liquid or low-melting-point solids. Throughout this disclosure, the three names are used without distinction. PEG is prepared by polymerization of ethylene oxide and is commercially available in a wide range of molecular weights from 300 g / mol to 10,000,000 g / mol. PEG and PEO with different molecular weights have been found to be used in different applications and have different physical properties (e.g., viscosity) due to the chain length effect, but their chemical properties are nearly identical. The polymer portion is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymer portions include polyethylene glycol (PEG), homopolymers or copolymers of PEG, monomethyl-substituted polymers of PEG (mPEG), or polyoxyethylene glycerol (POG). See Int. J. Hematology 68:1 (1998), Bioconjugate Chem. 6:150 (1995), and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). PEGs prepared for the purpose of extending half-lives, such as monomethoxy-terminated polyethylene glycol (mPEG), and monoactivated alkoxy-terminated polyalkylene oxides (POAs), as well as bisactivated polyethylene oxides (glycols) or other PEG derivatives, are also intended. Suitable polymers vary substantially by weight from about 200 to about 40,000 and are typically selected for the purposes of the present invention. In certain embodiments, PEG having a molecular weight of 200 to 2,000 daltons or 200 to 500 daltons is used.Different forms of PEG may also be used depending on the initiator used in the polymerization process, for example, common initiators include monofunctional methyl ether PEG, or methoxypoly(ethylene glycol) abbreviated as mPEG. Other suitable initiators are known in the art and are suitable for use in the present invention.

[0562] Low molecular weight PEGs are also available as pure oligomers, referred to as monodisperse, homogeneous, or distinct. These are used in specific embodiments of the present invention.

[0563] PEG is also available in different forms: branched PEG has 3 to 10 PEG chains emanating from a central core group, star-shaped PEG has 10 to 100 PEG chains emanating from a central core group, and comb-shaped PEG typically has multiple PEG chains grafted onto a polymer backbone. PEG can also be linear. The number often included in the name of PEG indicates its average molecular weight (for example, PEG with n=9 has an average molecular weight of approximately 400 daltons and is classified as PEG400).

[0564] As used herein, “PEGylation” is the action of conjugating a PEG structure to a hepcidin analog of the present invention (e.g., by covalent bond), and in certain embodiments, it is referred to as the “PEGylated hepcidin analog.” In certain embodiments, the PEG of the PEGylated side chain is a PEG having a molecular weight of about 200 to about 40,000. In certain embodiments, the PEG portion of the conjugated half-life extension portion is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, it is PEG11. In certain embodiments, the PEG of the PEGylated spacer is PEG3 or PEG8. In some embodiments, the spacer is PEGylated. In certain embodiments, the PEG of the PEGylated spacer is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of the PEGylated spacer is PEG3 or PEG8.

[0565] In some embodiments, the present invention comprises a hepcidin analog peptide (or its dimer) conjugated with PEG, which is covalently bonded, for example, via an amide, thiol, by click chemistry, or by any other suitable means known in the art. In certain embodiments, the PEG is bonded via an amide bond, and therefore, the specific PEG derivative used is appropriately functionalized. For example, in certain embodiments, PEG11, which is O-(2-aminoethyl)-O'-(2-carboxyethyl)-undecaethylene glycol, has both an amine and a carboxylic acid for bonding to the peptide of the present invention. In certain embodiments, PEG25 comprises a diacid and 25 glycol moieties.

[0566] Other suitable polymer 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 polymer moieties may be linear or branched. In some embodiments, they have molecular weights of 500 to 40,000 Da, for example, 500 to 10,000 Da, 1,000 to 5,000 Da, 10,000 to 20,000 Da, or 20,000 to 40,000 Da.

[0567] In some embodiments, the hepcidine analog of the present invention may comprise two or more such polymer moieties, in which case the total molecular weight of all such moieties is generally within the range provided above.

[0568] In some embodiments, the polymer moiety may be covalently bonded to the amino, carboxyl, or thiol groups of the amino acid side chains. Specific examples include the thiol groups of Cys residues and the epsilon-amino groups of Lys residues; carboxyl groups of Asp and Glu residues may also be used.

[0569] Those skilled in the art will be familiar with suitable techniques that can be used to carry out the conjugation reaction. For example, the PEG moiety having a methoxy group can be conjugated to a Cys thiol group by a maleimide bond using reagents commercially available from Nektar Therapeutics AL. See also WO2008 / 101017 and the references listed above for details on suitable chemicals. Maleimide-functionalized PEG can also be conjugated to the sulfhydryl group of the Cys residue's side chain.

[0570] Where used herein, disulfide bond oxidation can be a single-step or two-step process. Where used herein, for a single oxidation step, a trityl protecting group is often used during assembly, thereby enabling deprotection during cleavage, followed by solution oxidation. When a second disulfide bond is required, there is a choice between native oxidation or selective oxidation. For selective oxidation requiring orthogonal protecting groups, Acm and trityl are used as protecting groups for cysteine. Cleavage results in the removal of one protecting pair of cysteine, allowing oxidation of this pair. A second oxidative deprotection step is then performed on the cysteine-protected Acm group. For native oxidation, a trityl protecting group is used on all cysteine, allowing for the natural folding of the peptide.

[0571] Those skilled in the art will be familiar with suitable techniques that can be used to carry out the oxidation step.

[0572] In certain embodiments, the hepcidin analog of the present invention includes a half-life extension portion that may be selected from, but is not limited to, Ahx-Palm, PEG2-Palm, PEG11-Palm, isoGlu-Palm, dapa-Palm, isoGlu-lauric acid, isoGlu-myristic acid, and isoGlu-isovaleric acid.

[0573] In certain embodiments, the hepcidin analog comprises a half-life extension portion having the structure shown below, where n=0 to 24 or n=14 to 24. TIFF2026048851000491.tif16128

[0574] In certain embodiments, the hepcidin analog of the present invention includes a conjugated half-life extension portion shown in Table 3.

[0575] (Table 3) Exemplary half-life extension portion TIFF2026048851000492.tif107145TIFF2026048851000493.tif223143

[0576] In certain embodiments, the half-life extension portion is directly conjugated to a hepcidin analog, while in other embodiments, the half-life extension portion is conjugated to a hepcidin analog peptide via a linker portion, for example, one of those shown in Table 4.

[0577] (Table 4) Exemplary linker section* TIFF2026048851000494.tif173148TIFF2026048851000495.tif148148*(Peg) is -(OCH2CH2)-.

[0578] Regarding the linker structures shown in Table 7, references to n=1 to 24 or n=1 to 25 (e.g., listed in L4 or L5) indicate that n can be any integer within the specified range. Additional linker components that may be used are shown in the "Abbreviations" table.

[0579] In certain embodiments, the hepcidin analog of the present invention comprises one of the linker moieties shown in Table 4 and one of the half-life extension moieties shown in Table 3, and comprises one of the following combinations shown in Table 5.

[0580] (Table 5) Exemplary combinations of linker and half-life extension moieties in hepcidin analogs TIFF2026048851000496.tif216120TIFF2026048851000497.tif219123

[0581] In certain embodiments, the hepcidin analog comprises two or more linkers. In certain embodiments, the two or more linkers are concatemerized, i.e., bound to one another.

[0582] In related embodiments, the present invention includes a polynucleotide encoding a polypeptide having a peptide sequence present in any of the hepcidin analogs described herein.

[0583] Furthermore, the present invention includes vectors containing the polynucleotide of the present invention, such as expression vectors.

[0584] Treatment method In some embodiments, the present invention provides a method for treating a subject suffering from a disease or disorder related to dysregulation of hepcidin signaling, comprising administering a hepcidin analog of the present invention to the subject. In some embodiments, the hepcidin analog 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 suffering from a disease or disorder characterized by increased activity or expression of ferroportin, comprising administering to the subject a hepcidin analog or composition of the present invention in an amount sufficient to bind (partially or completely) to ferroportin in the subject and to agonize ferroportin or mimetic hepcidin. In one embodiment, a method is provided for treating a subject suffering from a disease or disorder characterized by dysregulation of iron metabolism, comprising administering a hepcidin analog or composition of the present invention to the subject.

[0585] In some embodiments, the methods of the present invention include providing a hepcidin analog or composition of the present invention to a subject in need. In certain embodiments, the subject in need is diagnosed with or determined to be at risk of developing a disease or disorder characterized by dysregulation of 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 certain embodiments, the subject is a mammal (e.g., human).

[0586] In certain embodiments, the disease or disorder is a disorder of iron metabolism, such as iron overload disease, iron deficiency, impaired iron distribution, or another disorder of iron metabolism, and other disorders potentially related to iron metabolism. In certain embodiments, iron metabolic disorders include hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemomodoverin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusion iron overload, thalassemia, intermediate thalassemia, alpha-thalassemia, beta-thalassemia, sideroblastic anemia, porphyria, cutaneous tarda porphyria, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital erythrocytic anemia, hypochromic microcytic anemia, sickle cell anemia, polycythemia vera (primary and secondary), and secondary erythrocytes. These include cytosis, chronic obstructive pulmonary disease (COPD), post-kidney transplantation, Chuvasi, HIF and PHD mutations, idiopathic myelodysplasia, pyruvate kinase deficiency, hypochromic microcytic anemia, transfusion-dependent anemia, hemolytic anemia, iron deficiency in obesity, other anemias, benign or malignant tumors that overproduce or induce hepcidin, hepcidin excess, Friedreich's ataxia, Gracil syndrome, Haller-Boden-Spats disease, Wilson's disease, pulmonary hemosiderin deposition, hepatocellular carcinoma, cancer (e.g., liver cancer), hepatitis, cirrhosis, pica, chronic renal failure, insulin resistance, diabetes mellitus, atherosclerosis, neurodegenerative diseases, dementia, multiple sclerosis, Parkinson's disease, Huntington's disease, or Alzheimer's disease.

[0587] In certain embodiments, the diseases and disorders are associated with iron overload diseases such as iron hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemomodoverin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusion iron overload, thalassemia, intermediate thalassemia, alpha-thalassemia, sickle cell disease, myelodysplasia, sideroblast infection, diabetic retinopathy, and pyruvate kinase deficiency.

[0588] In certain embodiments, the disease or disorder is not typically identified as iron-related. For example, hepcidin is highly expressed in mouse pancreas, suggesting that diabetes mellitus (type I or II), insulin resistance, impaired glucose tolerance, and other disorders may be ameliorated by treating the underlying iron metabolic disorder. See Ilyin, G. et al. (2003) FEBS Lett. 542 22-26, incorporated herein by reference. Thus, the peptides of the present invention may be used to treat these diseases and conditions. Those skilled in the art can readily determine whether a given disease can be treated with the peptides of the present invention using methods known in the art, including assays known in the art, such as the WO2004 / 092405 assay incorporated herein by reference, and assays that monitor hepcidin, hemoduberin, or iron levels and expression, as described in U.S. Patent No. 7,534,764, incorporated herein by reference.

[0589] In certain embodiments, the disease or disorder is postmenopausal osteoporosis.

[0590] In certain embodiments of the present invention, iron metabolism disorders are iron overload disorders, including hereditary hemochromatosis, iron-loaded anemia, alcoholic liver disease, heart disease and / or failure, cardiomyopathy, and chronic hepatitis C.

[0591] In certain embodiments, any of these diseases, disorders, or indications are caused by or related to hepcidin deficiency or iron excess.

[0592] In some embodiments, the method of the present invention includes providing a hepcidin analog of the present invention (i.e., a first therapeutic agent) in combination with a second therapeutic agent in a subject where such provision is required. In certain embodiments, the second therapeutic agent is provided to the subject before and / or simultaneously with and / or after the administration of the pharmaceutical composition to the subject. In certain embodiments, the second therapeutic agent is an iron chelating agent. In certain embodiments, the second therapeutic agent is selected from deferoxamine and deferasirox (Exjade®), which are iron chelating agents. In other embodiments, the method includes administering a third therapeutic agent to the subject.

[0593] The present invention provides compositions (e.g., pharmaceutical compositions) comprising one or more hepcidin analogs of the present invention and pharmaceutically acceptable carriers, excipients, or diluents. Pharmaceutically acceptable carriers, diluents, or excipients refer to non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or any type of formulation aid. Inhibition of microbial activity can be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. Inclusion of sugars and isotonic agents such as sodium chloride may also be desirable.

[0594] The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutically acceptable carriers. pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical industry 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 buffers may be, for example, phosphates, citrates, acetates, tris(hydroxymethyl)aminomethane (Tris), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine, or acetates (e.g., sodium acetate), or mixtures thereof. The term further encompasses any carriers listed in the United States Pharmacopeia for use in animals, including humans.

[0595] In certain embodiments, the composition comprises two or more hepcidin analogs disclosed herein. In certain embodiments, the combination is selected from one of the following: (i) any two or more hepcidin analog peptide monomers shown herein, (ii) any two or more hepcidin analog peptide dimers disclosed herein, (iii) any one or more hepcidin analog peptide monomers disclosed herein and any one or more hepcidin analog peptide dimers disclosed herein.

[0596] It should be understood that including a hepcidin analog of the present invention (i.e., one or more hepcidin analog peptide monomers or one or more hepcidin analog peptide dimers of the present invention) in a pharmaceutical composition also includes including a pharmaceutically acceptable salt or solvate of the hepcidin analog of the present invention. In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, excipients, or vehicles.

[0597] In certain embodiments, the present invention provides pharmaceutical compositions comprising a hepcidin analog or a pharmaceutically acceptable salt or solvate thereof for treating various conditions, diseases, or disorders disclosed herein or elsewhere (see, for example, the therapeutic methods herein). In certain embodiments, the present invention provides pharmaceutical compositions comprising a hepcidin analog peptide monomer or a pharmaceutically acceptable salt or solvate thereof for treating various conditions, diseases, or disorders disclosed elsewhere herein (see, for example, the therapeutic methods herein). In certain embodiments, the present invention provides pharmaceutical compositions comprising a hepcidin analog peptide dimer or a pharmaceutically acceptable salt or solvate thereof for treating various conditions, diseases, or disorders disclosed herein.

[0598] The hepcidin analogs of the present invention are suitable for administration with or without storage and can be formulated as pharmaceutical compositions typically containing a therapeutically effective amount of at least one hepcidin analog of the present invention together with a pharmaceutically acceptable carrier, excipient, or vehicle.

[0599] In some embodiments, the hepcidin analog pharmaceutical compositions of the present invention are unit dosage forms. In such forms, the composition is divided into unit doses containing an appropriate amount(s) of the active ingredient. The unit dosage form may be provided as a packaged preparation, the package containing separate amounts of the preparation, e.g., packaged tablets, capsules, or powders in a vial or ampoule. The unit dosage form may also be, for example, a capsule, cachet, or tablet itself, or any appropriate number of these packaging forms. The unit dosage form may also be provided in an injectable form for single-dose administration, e.g., in the form of a pen device containing a liquid-phase (typically aqueous) composition. The composition may be formulated for any preferred route and means of administration, e.g., any one of the routes and means of administration disclosed herein.

[0600] In certain embodiments, a hepcidin analog or a pharmaceutical composition containing a hepcidin analog is suspended in a sustained-release matrix. The sustained-release matrix used herein is a matrix made of a material (usually a polymer) that is degradable by enzymatic hydrolysis, acid-base hydrolysis, or dissolution. Once inserted into the body, enzymes and body fluids act on this matrix. The sustained-release matrix is ​​preferably selected from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolides (polymers of glycolic acid), polylactidecoglycolides (copolymers of lactic acid and glycolic acid), polyacid anhydrides, 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, and isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicones. A preferred biodegradable matrix is ​​one of the following: polylactide, polyglycolide, or polylactide co-glycolide (a copolymer of lactic acid and glycolic acid).

[0601] In certain embodiments, the composition is administered parenterally, subcutaneously, or orally. In certain embodiments, the composition is administered orally, intracisionally, intravaginally, intraperitoneally, intrarectally, topically (including delivery by intravitreal, intranasal, and inhalation, such as by powder, ointment, drops, suppositories, or transdermal patch), or buccally. As used herein, the term “parenteral” refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions. Accordingly, in certain embodiments, the composition is formulated for delivery by any of these routes of administration.

[0602] In certain embodiments, a pharmaceutical composition for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or sterile powder for reconstitution into a sterile injectable solution or dispersion immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, beta-cyclodextrin, vegetable oils (olive oil), and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Long-term absorption of the injectable pharmaceutical dosage form can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0603] Injectable depot formulations include those prepared by forming a microcapsule matrix of hepcidine analogs in one or more biodegradable polymers such as polylactide-polyglycolide, poly(orthoester), poly(anhydrous), and (poly)glycols such as PEG. The release rate of the hepcidine analog can be controlled depending on the peptide-to-polymer ratio and the properties of the specific polymer used. Depot-injectable formulations are also prepared by capturing the hepcidine analogs in liposomes or microemulsions that are compatible with body tissues.

[0604] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed immediately before use in sterile water or other sterile injectable media.

[0605] The hepcidin analog 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 monolayers or multilayers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipids capable of forming liposomes may be used. The liposomal composition of the present invention may include stabilizers, preservatives, excipients, etc., in addition to the hepcidin analog of the present invention. In certain embodiments, the lipids include phospholipids containing both natural and synthetic phosphatidylcholine (lecithin) and serine. Methods for forming liposomes are known in the art.

[0606] The pharmaceutical compositions used in the present invention, which are suitable for parenteral administration, may include sterile aqueous solutions and / or suspensions of peptide inhibitors that are isotonic with the recipient's blood, typically using sodium chloride, glycerin, glucose, mannitol, sorbitol, etc.

[0607] In some embodiments, the present invention provides pharmaceutical compositions for oral delivery. The compositions and hepcidin analogs of the present invention can be prepared for oral administration according to any of the methods, techniques and / or delivery vehicles described herein. Furthermore, those skilled in the art will understand that the hepcidin analogs of the present invention, although not disclosed herein, are known in the art and can be modified or integrated into systems or delivery vehicles suitable for use in the oral delivery of peptides.

[0608] In certain embodiments, formulations for oral administration may include adjuvants to artificially increase permeability of the intestinal wall (e.g., nonionic surfactants such as resorcinol and / or polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether), and / or enzyme inhibitors to inhibit enzymatic degradation (e.g., pancreatic trypsin inhibitors, diisopropyl fluorophosphate (DFF), or tracylol). In certain embodiments, hepcidin analogs in solid dosage forms for oral administration may be mixed with at least one additive such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, acacia gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms may also contain other types of additives, such as inert diluents, lubricants, such as magnesium stearate, parabens, preservatives, such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants, such as cysteine, disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or fragrances.

[0609] In certain embodiments, an oral dosage form or unit dose suitable for use with the hepcidin analog of the present invention may comprise a mixture of the hepcidin analog with a non-pharmacological component or excipient, and other non-reusable materials that may be considered components or packaging. The oral composition may comprise at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, an oral dosage form comprising an effective amount of the hepcidin analog is provided, and the dosage form comprises at least one of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. In some cases, an oral dosage form is provided that is designed and configured to achieve delayed release of the hepcidin analog in the small intestine and / or colon of the subject.

[0610] In one embodiment, an oral pharmaceutical composition comprising the hepcidin analog of the present invention comprises an enteric coating designed to delay the release of the hepcidin analog in the small intestine. In at least some embodiments, a pharmaceutical composition is provided comprising the hepcidin analog of the present invention and a protease inhibitor such as aprotinin in a delayed-release formulation. In some cases, the pharmaceutical composition of the present invention comprises an enteric coating 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 a dissociable carboxyl group, such as cellulose derivatives including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, as well as similar derivatives of cellulose and other carbohydrate polymers.

[0611] In one embodiment, a pharmaceutical composition comprising the hepcidin analog of the present invention is provided with an enteric coating, which is designed to protect and release the pharmaceutical composition in a controlled manner within the lower digestive system of the target, thereby avoiding systemic adverse reactions. In addition to enteric coating, the hepcidin analog of the present invention may be encapsulated, coated, engaged, or otherwise associated within any suitable oral drug delivery system or component. For example, in some embodiments, the hepcidin analog of the present invention is provided in a lipid carrier system comprising at least one of polymer hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

[0612] To overcome peptide degradation in the small intestine, some embodiments of the present invention include a hydrogel polymer carrier system containing the hepcidin analog of the present invention, thereby protecting the hepcidin analog from protein degradation in the small intestine and / or colon. The hepcidin analog of the present invention may be further formulated for use in conjunction with carrier systems designed to increase solubility and enhance intestinal absorption of peptides. These methods include the use of liposomes, micelles, and nanoparticles to increase GI tube penetration of peptides.

[0613] Various bioreactive systems can be combined with one or more hepcidin analogs of the present invention to provide pharmaceuticals for oral delivery. In some embodiments, the hepcidin analogs of the present invention are used in combination with bioreactive systems such as hydrogels and mucosal adhesive polymers having hydrogen bonding groups (e.g., PEG, poly(methacrylic acid [PMAA], cellulose, Eudragit®, chitosan, and alginates) to provide therapeutic agents for oral administration. Other embodiments include methods for optimizing or extending the drug residence time of the hepcidin analogs disclosed herein, wherein the surface of the hepcidin analog is modified to include mucosal adhesive properties via hydrogen bonding, polymers having linked mucins, and / or hydrophobic interactions. These modified peptide molecules can demonstrate increased drug residence time in a subject according to the desired features of the present invention. Furthermore, targeted mucosal adhesion systems can specifically bind to receptors on the surface of intestinal cells and M cells, thereby further increasing the uptake of particles containing the hepcidin analog.

[0614] Other embodiments include methods for oral delivery of the hepcidin analog of the present invention, in which the hepcidin analog is provided to subjects in combination with a permeabiliser that facilitates the transport of the peptide across the intestinal mucosa by increasing paracellular or transcellular permeation. For example, in one embodiment, the permeabiliser is combined with the hepcidin analog, and the permeabiliser comprises at least one of long-chain fatty acids, bile salts, amphiphilic surfactants, and chelating agents. In one embodiment, a permeabiliser comprising sodium N-[hydroxybenzoyl)amino]caprylate is used to form a weak non-covalent association with the hepcidin analog of the present invention, and the permeabiliser acts favorably for membrane transport and further dissociation once it reaches the bloodstream. In another embodiment, the hepcidin analog of the present invention is conjugated to oligoarginine, thereby increasing the cellular permeability of the peptide into various cell types. Furthermore, in at least one embodiment, a non-covalent bond is provided between the peptide inhibitor of the present invention and a penetration enhancer selected from the group consisting of cyclodextrin (CD) and dendrimers, the penetration enhancer reducing peptide aggregation and increasing the stability and solubility of the hepcidin analog molecule.

[0615] Other embodiments of the present invention provide methods for treating a subject with a hepcidin analog of the present invention having an increased half-life. In one embodiment, the present invention provides a hepcidin analog 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 a therapeutically effective dose administered once daily (qd) or twice daily (bid). In another embodiment, the hepcidin analog has a half-life of three days or more, sufficient for a therapeutically effective dose administered once weekly (qw). Furthermore, in yet another embodiment, the hepcidin analog has a half-life of eight days or more, sufficient for a therapeutically effective dose administered once every two weeks (biw) or once a month. In yet another embodiment, the hepcidin analog is derivatized or modified so that it has a longer half-life compared to a non-derivativeated or unmodified hepcidin analog. In yet another embodiment, the hepcidin analog includes one or more chemical modifications to increase the serum half-life.

[0616] When used in at least one of the therapeutic or delivery systems described herein, the hepcidin analogs of the present invention may be used in pure form or in pharmaceutically acceptable salt forms, if such forms exist.

[0617] Dosage The total daily dose of the hepcidin analogs and compositions of the present invention can be determined by the attending physician within the bounds of sound medical judgment. The specific therapeutically effective dose level for any particular subject depends on a) the disorder being treated and its severity, b) the activity of the particular compound used, c) the particular composition used, the patient's age, weight, overall health, sex, and diet, d) the timing of administration, route of administration, and excretion rate of the particular hepcidin analog used, e) the duration of treatment, f) drugs used in combination with or concurrently with the particular hepcidin analog used, as well as similar factors well known in the medical field.

[0618] In certain embodiments, the total daily dose of the hepcidin analog of the present invention administered to a human or other mammalian host in a single or divided dose may be, for example, 0.0001 to 300 mg / kg body weight or 1 to 300 mg / kg body weight per day. In certain embodiments, the dose of the hepcidin analog of the present invention may be in the range of about 0.0001 to about 100 mg / kg body weight per day, for example, about 0.0005 to about 50 mg / kg body weight per day, for example, about 0.001 to about 10 mg / kg body weight per day, for example, about 0.01 to about 1 mg / kg body weight per day / day, and may be administered in one or more doses, such as 1 to 3 doses. In certain embodiments, the total dose may be, for example, 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 per week to a human patient, about once or twice a week. In certain embodiments, the total dose is in the range of approximately 1 mg to 5 mg, or approximately 1 mg to 3 mg, or approximately 2 mg to 3 mg per human patient, for example, approximately once a week.

[0619] In various embodiments, the hepcidin analogs of the present invention may be administered continuously (e.g., by intravenous administration or another continuous drug administration method), or at intervals, typically at regular intervals, depending on the desired dosage and pharmaceutical composition selected by those skilled in the art for a particular subject. Regular dosing intervals include, for example, once daily, twice daily, once every two days, once every three days, once every four days, once every five days or once every six days, once or twice per week, once or twice per month, and so on.

[0620] Such regular hepcidin analog administration regimens of the present invention may be advantageously interrupted for a period of time to reduce the level of the drug or discontinue drug administration, often referred to as “taking a drug break,” in certain situations, such as during chronic long-term administration. Drug breaks are useful, for example, to maintain or restore sensitivity to the drug, particularly during long-term chronic treatment, or to reduce undesirable side effects of long-term chronic treatment of the subject with the drug. The timing of the drug break depends on the timing of the regular administration regimen and the purpose of taking the drug break (e.g., to restore drug sensitivity and / or to reduce undesirable side effects of continuous long-term administration). In some embodiments, the drug break may be a reduction in the dose of the drug (e.g., below the therapeutically effective dose over a specific interval). In other embodiments, the administration of the drug is stopped at a certain interval before administration is restarted using the same or a different administration regimen (e.g., a lower or higher dose and / or administration frequency). Thus, drug breaks of the present invention can be selected from a wide range of periods and administration regimens. Exemplary drug-free periods include those lasting two days or more, one week or more, or one month or more, up to approximately 24 months. Therefore, for example, a regular daily dosing regimen using the peptide, peptide analogue, or dimer of the present invention may be interrupted by a drug-free period of one, two, or four weeks, after which the previous regular dosing regimen (e.g., a daily or once-weekly dosing regimen) is resumed. Various other drug-free regimens are intended to be useful for administering the hepcidin analogue of the present invention.

[0621] Therefore, hepcidin analogs can be delivered by a dosing regime that includes two or more dosing periods separated by their respective rest periods.

[0622] During each administration period, the hepcidin analog is administered to the recipient in a therapeutically effective dose according to a predetermined administration pattern. The administration pattern may include continuous administration of the drug to the recipient over the duration of the administration period. Alternatively, the administration pattern may include administration of multiple doses of the hepcidin analog to the recipient, with intervals set by the administration interval.

[0623] The administration pattern may include at least two doses per administration period, at least five doses per administration period, at least ten doses per administration period, at least twenty doses per administration period, at least thirty doses per administration period, or more.

[0624] The above-mentioned dosing interval may be a regular dosing interval, as set above, including once daily, twice daily, once every two days, once every three days, once every four days, once every five days or once every six days, once or twice a week, once or twice a month, or a regular and even less frequent dosing interval, depending on the specific dosage form, bioavailability and pharmacokinetic profile of the hepcidin analog of the present invention.

[0625] The administration period may be at least 2 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer.

[0626] If the dosing pattern involves multiple doses, the duration of the following drug-free period will be longer than the dosing interval used in that dosing pattern. If the dosing intervals are irregular, the duration of the drug-free period may be longer than the average interval between doses throughout the dosing period. Alternatively, the duration of the drug-free period may be longer than the longest interval between consecutive doses during the dosing period.

[0627] The drug-free period may be at least twice the relevant dosing interval (or its average), at least three times, at least four times, at least five times, at least ten times, or at least twenty times the relevant dosing interval or its average.

[0628] Within these constraints, the drug-free period may have a duration of at least 2 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer, depending on the administration pattern during the previous administration period.

[0629] A dosing regime consists of at least two dosing periods. Consecutive dosing periods are separated by rest periods. Therefore, a dosing regime may consist of at least three, at least four, at least five, at least ten, at least fifteen, at least twenty, at least twenty-five, or at least thirty or more dosing periods, each separated by a rest period.

[0630] While the same dosing pattern may be used during consecutive dosing periods, this is not always desirable or necessary. However, when other drugs or activators are administered in combination with the hepcidin analog of the present invention, typically the same combination of drugs or activators is given during consecutive dosing periods. In certain embodiments, the recipient is human.

[0631] In some embodiments, the present invention provides compositions and agents comprising at least one hepcidin analog disclosed herein. In some embodiments, the present invention provides a method for producing an agent comprising at least one hepcidin analog disclosed herein for the treatment of iron metabolic disorders such as iron overload disease. In some embodiments, the present invention provides a method for producing an agent comprising at least one hepcidin analog disclosed herein for the treatment of diabetes mellitus (type I or type II), insulin resistance, or impaired glucose tolerance. Also provided are methods for treating iron metabolic disorders in mammalian subjects, preferably human subjects, comprising administering at least one hepcidin analog or composition disclosed herein to the subject. In some embodiments, the hepcidin analog or composition is administered in a therapeutically effective dose. Also provided are methods for treating diabetes mellitus (type I or type II), insulin resistance, or impaired glucose tolerance in mammalian subjects, preferably human subjects, comprising administering at least one hepcidin analog or composition disclosed herein to the subject. In some embodiments, the hepcidin analog or composition is administered in a therapeutically effective dose.

[0632] In some embodiments, the present invention provides a process for producing hepcidin analogs or hepcidin analog compositions (e.g., pharmaceutical compositions) disclosed herein.

[0633] In some embodiments, the present invention provides a device comprising at least one hepcidin analog of the present invention or a pharmaceutically acceptable salt or solvate thereof for target delivery of the hepcidin analog.

[0634] In some embodiments, the present invention provides a method for binding to ferroportin or inducing its internalization and degradation, comprising contacting ferroportin with at least one hepcidin analog or hepcidin analog composition disclosed herein.

[0635] In some embodiments, the present invention provides a method for binding ferroportin to block pore and transporter function without causing ferroportin internalization. Such a method involves contacting ferroportin with at least one hepcidin analog or hepcidin analog composition disclosed herein.

[0636] In some embodiments, the present invention provides a kit comprising at least one hepcidin analog or hepcidin analog composition (e.g., a pharmaceutical composition) as disclosed herein, packaged together with a reagent, a device, instructions, or a combination thereof.

[0637] In some embodiments, the present invention provides a method for administering the hepcidin analog or hepcidin analog composition (e.g., a pharmaceutical composition) to a subject by means of an implant or osmotic pump, by a cartridge or micropump, or by other means recognized by those skilled in the art, as is well known in the art.

[0638] In some embodiments, the present invention provides a complex comprising at least one hepcidin analog disclosed herein that binds to ferroportin, preferably human ferroportin, or an antibody, such as a hepcidin analog disclosed herein, Hep25, or a combination thereof.

[0639] In some embodiments, the hepcidin analog of the present invention is measured at less than 500 nM in an FPN endocrine assay (e.g., EC2). 50 Those skilled in the art will understand that the function of a hepcidin analog depends on the tertiary structure and binding surface of the presented hepcidin analog. Therefore, it is possible to make slight modifications to the sequence encoding a hepcidin analog that does not affect folding or is not on the binding surface, and that maintains function. In other embodiments, the present invention provides a hepcidin analog having 85% or more (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%) identity or homology to the amino acid sequence of any hepcidin analog described herein, exhibiting activity (e.g., hepcidin activity) or alleviating symptoms of a disease or indication in which hepcidin is involved.

[0640] In other embodiments, the present invention provides hepcidin analogs having 85% or more identity or homology (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%) to the amino acid sequence of any hepcidin analog presented herein, or to a peptide comprising any one of the formulas or hepcidin analogs described herein.

[0641] In some embodiments, the hepcidin analogs of the present invention may comprise functional fragments or variants thereof having up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions compared to one or more of the specific peptide analog sequences described herein.

[0642] In addition to the methods described herein in the examples, the hepcidin analogs of the present invention may be prepared by methods known in the art, including chemical synthesis, biosynthesis, in vitro synthesis using recombinant DNA methods, and solid-phase synthesis. For example, see Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, JK Setlow ed., Plenum Press, NY, pp. 1-19, incorporated herein by reference; Merrifield (1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:5131-5135; and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2nd ed. Pierce, Rockford, IL. The hepcidin analogs 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 chromatography 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 incorporated herein by reference. Alternatively, the hepcidin analogs of the present invention may be prepared by recombinant DNA techniques known in the art. Thus, polynucleotides encoding 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 in an environment different from the environment in which they naturally occur. [Examples]

[0643] The following examples illustrate specific embodiments of the present invention. Unless otherwise described in detail, the following examples were carried out using standard techniques that are well known and routine to those skilled in the art. It should be understood that these examples are for illustrative purposes only and are not intended to limit the conditions or scope of the present invention in any way. Therefore, they should never be construed as limiting the scope of the present invention.

[0644] Abbreviation: DCM: Dichloromethane DMF: N,N-dimethylformamide NMP: N-methylpyrrolidone HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tet...

Claims

1. Formula I': R １ -Xbb1-Thr-X3-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R ２ (I) A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R １ is hydrogen, C １ to C ６ alkyl, C ６ to C １２ aryl, C ６ to C １２ aryl-C １ to C ６ alkyl, C １ to C ２０ alkanoyl, C ２ to C ２０ alkenoyl, or C １ to C ２０ cycloalkanoyl; R ２ However, NH ２ or OH; Xbb1 is Asp, isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, bGlu, Gla, or Glp; X3 is His or a substitution His; Each Xaa1 and Xaa2 is independently Ala, Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is nonexistent, Lys, D-Lys, (D)Leu, (D)Ala, a-Me-Lys, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5 (L1Z), B5 is Lys, D-Lys, or Lys (Ac), Xaa2 is B7, B7 is either Glu or does not exist; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-Mecys, or Pen; B4 is Gly, N-substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and PEG is -[C(O)-CH ２ - (Peg) ｎ -N(H)] ｍ -, or -[C(O)-CH ２ -CH ２ - (Peg) ｎ -N(H)] ｍ And Peg is -OCH ２ CH ２ -, where m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, where each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly; Y1 is Abu, Cys, HomoCys, (D)Cys, NMecys, aMeCys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Naal is 1-naphthylalanine, 2-Naal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted bhPhe is β-homophenylalanine, and phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-L-b-homotryptophan, a-methyl-b-homotryptophan, or b-homotryptophan, which is substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R １ , PEG-encoded in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; However, if Xbb1 is Asp, R １ However, C ２ ~C ２０ It is Alkenoil. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

2. Xbb1 is Asp, R １ However, C ２ ~C ２０ A hepcidin analog comprising the peptide described in claim 1, which is an alkenoyl.

3. A hepcidin analog comprising the peptide according to claim 1, wherein Xbb1 is (D)Glu or (D)IsoGlu.

4. A hepcidin analog comprising the peptide according to claim 1, wherein Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp.

5. A hepcidin analog comprising the peptide according to claim 1, wherein B1 is Dpa.

6. A hepcidin analog comprising the peptide according to claim 1, wherein Xaa1 is B5 (L1Z), B5 is Lys, D-Lys, Dap, or Dap-Dap, and Xaa2 is B7, and B7 is Glu or absent.

7. A hepcidin analog comprising the peptide described in claim 1, which is Pro or NPC.

8. A hepcidin analog comprising the peptide according to claim 1, wherein X7 is Ile.

9. A hepcidin analog comprising the peptide according to claim 1, wherein B9 is Phe or bhPhe.

10. A hepcidin analog comprising the peptide according to claim 1, wherein J is absent, any amino acid, or a peptide chain consisting of 1 to 5 amino acids, and each amino acid is independently selected from Pro, (D)Pro, hydroxyPro, hydroxy(D)Pro, Arg, MeArg, Lys, (D)Lys, Lys(Ac), (D)Lys(Ac), Ser, MeSer, Sar, and Gly.

11. J is Arg, Lys, D-Lys, Spiro_pip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO: 249), -Pro-Arg-Ser -Lys-Sar- (SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly- (SEQ ID NO: 251), -Pro-Lys(Ac)-, -Pro-(D)Lys(Ac)-, -Pro-Arg-Ser-Lys(Ac)- (SEQ ID NO: 249), -Pro-Arg-Ser-Lys(Ac)-Sar- (SEQ ID NO: 250), -Pro-Arg- Ser-Lys(Ac)-Gly-,-hydroxyPro-Arg-Ser-Lys-Gly-(SEQ ID NO: 251),-Pro-MeArg-Ser-Lys-Gly-,-Pro-Arg-MeSer-Lys-Gly-(SEQ ID NO: 251),(SEQ ID NO: 251),-Pro-Lys(Ac)-Ser-Lys(Ac)-,-Pro-Lys(A c) A hepcidin analog comprising the peptide according to claim 1, wherein J is or is absent, or J is any amino acid.

12. A hepcidin analog comprising the peptide according to claim 1, wherein J is Arg, Lys, D-Lys, Spiro_pip, Arg(nitro), Arg(dimethyl), Cit, Pro(4-amino), Cav, Pro-, Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar- (SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly- (SEQ ID NO: 251), or J is any amino acid.

13. Formula I: R １ -Xbb1-Thr-His-B1-B2-B3-B4-Xaa1-B6-Xaa2-J-Y1-Y2-R ２ (I) A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R １ However, hydrogen, C １ ~C ６ Alkyl, C ６ ~C １２ Ariel, C ６ ~C １２ Aryl-C １ ~C ６ Alkyl, C １ ~C ２０ Alkanoyl, or C １ ~C ２０ It is a cycloalkanoyl; R ２ However, NH ２ or OH; Xbb1 is isoAsp, Asp(OMe), Gly, substituted Gly, Glu, substituted Glu, bhGlu, bGlu, Gla, or Glp; Each Xaa1 and Xaa2 is independently Gly, N-substituted Gly, Lys, (D)Lys, Lys(Ac), or (D)Lys(Ac). or Xaa1 is B5, and B5 is nonexistent, Lys, D-Lys, (D)Leu, (D)Ala, or Lys(Ac), and Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or Xaa1 is B5 (L1Z), B5 is Lys, D-Lys, or Lys (Ac), Xaa2 is B7, B7 is either Glu or does not exist; Each of B1 and B6 is independently Gly, substituted Gly, Phe, substituted Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B3 is Cys, homocys, (D)cys, a-Mecys, or Pen; B4 is Gly, N-substitution Gly, Ile, (Me)Ile, Val, Leu, or NLeu; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and PEG is -[C(O)-CH ２ - (Peg) ｎ -N(H)] ｍ -, or -[C(O)-CH ２ -CH ２ - (Peg) ｎ -N(H)] ｍ - and Peg is -OCH ２ CH ２ -, where m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is either Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar- (SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly- (SEQ ID NO: 251), -His-(D)Phe-Arg-Trp-Cys-, or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMecys, aMecys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Naal is 1-naphthylalanine, 2-Naal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted bhPhe is β-homophenylalanine, and phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-L-b-homotryptophan, a-methyl-b-homotryptophan, or b-homotryptophan, which is substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I is optionally R １ , PEG-encoded in one or more of B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

14. The hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each Xaa1 and Xaa2 is independently Lys, Lys(Ac), (D)Lys, or (D)Lys(Ac).

15. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is Lys(Ac) and Xaa2 is (D)Lys(Ac).

16. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5, and B5 is absent, Lys, or D-Lys, and Xaa2 is B7 (L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

17. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5 (L1Z), B5 is Lys or D-Lys, Xaa2 is B7, and B7 is Glu or absent.

18. The aforementioned peptide is given by formula A-I: R １ -Xbb1-Thr-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R ２ (A-I) This is due to, During the ceremony: R １ , R ２ , B1 to B6, L1, Z, J, Y1, and Y2 are as described in claim 1; B7 is either Lys or D-Lys; Here: i) The peptide optionally contains one or more R １ PEG is encapsulated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Ph, then B5 is not Lys. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

19. The aforementioned peptide is given by formula B-I: R １ -Xbb1-Thr-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R ２ (B-I) This is due to, During the ceremony: R １ , R ２ , B1 to B6, L1, Z, J, Y1, and Y2 are as described in claim 1; Here: i) The peptide of formula I optionally contains one or more R １ , B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2 are PEG-encoded; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is either Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (sequence number 249) or does not exist. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

20. A hepcidin analog according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is F, Dpa, BIP, or bhPhe, B2 is Pro, NCP, (D)Pro, or (D)NCP, B3 is Cys, a-MeCys, or homoCys, B4 is Ile, B5 is Lys, or (D)Lys, B6 is Phe, substituted Phe, bhPhe, or 2Pal, and B7 is Lys or (D)Lys.

21. A hepcidin analog according to any one of claims 1 to 7, wherein B2 is Pro or NPC, B3 is Cys, B4 is Ile, and B6 is Phe, bhPhe, or 2Pal, or a pharmaceutically acceptable salt or solvate thereof.

22. B7(L1Z) is -N(H)C[CH ２ (CH ２ CH ２ CH ２ ) ｍ A hepcidin analog according to any one of claims 4 to 9, wherein N(H)L1Z](H)-C(O)- and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof.

23. B7(L1Z) is -N(H)C[CH ２ A hepcidin analog according to any one of claims 4 to 9, wherein the compound is N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof.

24. B7(L1Z) is -N(H)C[CH ２ CH ２ CH ２ CH ２ A hepcidin analog according to any one of claims 4 to 9, wherein the compound is N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof.

25. The peptide is of formula IV or V: R １ -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (IV), or R １ -Xbb1-Thr-His-B1-Pro-Cys-Ile-B5-B6-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (V) This is due to, During the ceremony: R １ , R ２ , L1, Z, J, Y1, and Y2 are as set forth in claim 1; B1 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), B5 is (D)Lys, and B6 is Phe, bhPhe, 2Pal. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

26. A hepcidin analog according to claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein B5 is (D) Lys.

27. The peptide is of formula VI or CIIb: R １ -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (VI), or R １ -Xbb1-Thr-His-B1-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (VII) This is due to, During the ceremony: R １ , R ２ , L1, Z, J, Y1, and Y2 are as set forth in claim 1; B1 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), and B6 is Phe, bhPhe, or 2Pal. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

28. A hepcidin analog according to any one of claims 13 to 15, wherein B1 is Phe, Phe(4-F), Phe(4-CF3), or Phe(2,3,5-trifluoro), or a pharmaceutically acceptable salt or solvate thereof.

29. A hepcidin analog according to any one of claims 13 to 15, wherein B1 is Dpa, or a pharmaceutically acceptable salt or solvate thereof.

30. The peptide is of formula VIII or IX: R １ -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-B6-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (VIII), or ( １ . ________________________| ２ ヨ ２ ヨ ２ ヨ ２ (())___________________________________________________ ２ (=) This is due to, During the ceremony: R １ , R ２ , L1, Z, J, Y1, and Y2 are as set forth in claim 1; B6 is Phe, Phe(4-F), Phe(4-CF3), Phe(2,3,5-trifluoro), bhPhe, 2Pal. A hepcidin analog according to claim 4, or a pharmaceutically acceptable salt or solvate thereof.

31. A hepcidin analog according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is Phe.

32. A hepcidin analog according to any one of claims 1 to 18, wherein B6 is bhPhe, or a pharmaceutically acceptable salt or solvate thereof.

33. The peptide is of formula Xa, Xb, Xc, or Xd: R １ -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (Xa)、 R １ -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-Phe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (Xb)、 R １ -Xbb1-Thr-His-F-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (Xc)、 R １ -Xbb1-Thr-His-Dpa-Pro-Cys-Ile-(D)Lys-bhPhe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (Xd) This is due to, During the ceremony: R １ , R ２ L1, Z, J, Y1, and Y2 are as described in claim 1. A hepcidin analog according to any one of claims 13 to 20, or a pharmaceutically acceptable salt or solvate thereof.

34. A hepcidin analog according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (SEQ ID NO: 253), -Pro-Arg-Ser-Lys-Cys- (SEQ ID NO: 254), -His-(D)Phe-Arg-Trp-Cys-, or -Pro-Arg-Ser-Lys-Sar-Cys- (SEQ ID NO: 255).

35. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-, or a pharmaceutically acceptable salt or solvate thereof.

36. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Cys-(D)Lys-, or a pharmaceutically acceptable salt or solvate thereof.

37. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys- (SEQ ID NO: 254), or a pharmaceutically acceptable salt or solvate thereof.

38. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Pro-Arg-Ser-Lys-Cys-Lys- (SEQ ID NO: 255), or a pharmaceutically acceptable salt or solvate thereof.

39. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Pro-Cys-, or a pharmaceutically acceptable salt or solvate thereof.

40. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -Cys-, or a pharmaceutically acceptable salt or solvate thereof.

41. A hepcidin analog according to any one of claims 1 to 21, wherein -J-Y1-Y2- is -(D)Lys-Pen-, or a pharmaceutically acceptable salt or solvate thereof.

42. A hepcidin analog according to any one of claims 1 to 29, wherein L1 is a single bond, or a pharmaceutically acceptable salt or solvate thereof.

43. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu.

44. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is Ahx.

45. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-Ahx.

46. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG.

47. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG-Ahx.

48. A hepcidin analog according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-PEG-Ahx.

49. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein PEG is -[C(O)-CH2-(PEG)n-N(H)]m- or -[C(O)-CH2-CH2-(PEG)n-N(H)]m-, PEG is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100, or 10K, 20K, or 30K.

50. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

51. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

52. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

53. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.

54. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 8.

55. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 11.

56. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 12.

57. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 20 K.

58. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 1PEG2, and 1PEG2 is -C(O)-CH2-(PEG)2-N(H)-.

59. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 2PEG2, and 2PEG2 is -C(O)-CH2-CH2-(PEG)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

60. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 1Peg2-1Peg2, and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

61. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-, or a pharmaceutically acceptable salt or solvate thereof.

62. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 2PEG4, and 2PEG4 is -C(O)-CH2-CH2-(PEG)4-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

63. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 1PEG8, and 1PEG8 is -C(O)-CH2-(PEG)8-N(H)-, or -[C(O)-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

64. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 2PEG8, and 2PEG8 is -C(O)-CH2-CH2-(PEG)8-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

65. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 1PEG11, and 1PEG11 is -C(O)-CH2-(PEG)11-N(H)-, or -[C(O)-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

66. A hepcidin analog according to any one of claims 1 to 36, wherein PEG is 2PEG11, and 2PEG11 is -C(O)-CH2-CH2-(PEG)11-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)11-NH]-.

67. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, 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]-.

68. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Lys, the -C(O)- of PEG is bound to the Ne of Lys.

69. The hepcidin analog according to any one of claims 1 to 36, wherein when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu.

70. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx.

71. A hepcidin analog according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Palm, the -N(H)- of PEG is bound to the -C(O)- of Palm.

72. A hepcidin analog according to any one of claims 1 to 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Palm.

73. A hepcidin analog according to any one of claims 1 to 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a diacid.

74. A hepcidin analog according to any one of claims 1 to 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a C8-C20 diacid.

75. Z is a C8-C20 diacid, where one of the acid groups is bonded to L1, and the other acid group is a free -C(O) ２ A hepcidin analog according to any one of claims 1 to 59, wherein H is present, or a pharmaceutically acceptable salt or solvate thereof.

76. A hepcidin analog according to any one of claims 73 to 75, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a C10, C12, C14, C16, or C18 diacid.

77. The aforementioned peptide is given by formula XXI: R １ -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7-J-Y1-Y2-R ２ (XXI) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as described in claim 1; R １ However, hydrogen, C １ ~C ６ Alkyl, C ６ ~C １２ Ariel, C ６ ~C １２ Aryl-C １ ~C ６ Alkyl, C １ ~C ２０ Alkanoyl, C ２ ~C ２０ Alkenoyl, or C １ ~C ２０ It is a cycloalkanoyl; R ２ However, NH ２ or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is either Glu or does not exist. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

78. -L1Z is, -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -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, During the ceremony: PEG11_OMe is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) １１ -OMe] and 1PEG2 is -C(O)-CH ２ - (OCH ２ CH ２ ) ２ -NH-, PEG4 is -C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) ４ -NH-, PEG8 is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) ８ -NH-, 1PEG8 is -[C(O)-CH ２ - (OCH ２ CH ２ ) ８ -NH-, PEG12 is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) １２ -NH-, Ado is -[C(O)-(CH ２ ) １１ -NH]- Cn acid is -C(O)(CH ２ ) ｎ－２ -CH ３ And the C18 acid is -C(O)-(CH ２ ) １６ -Me, Palm is -C(O)-(CH ２ ) １４ -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, And, Ahx is -[C(O)-(CH ２ ) ５ -NH]- is, A hepcidin analog according to any one of claims 1 to 77, or a pharmaceutically acceptable salt or solvate thereof.

79. -L1Z is, -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, During the ceremony: 1PEG2, 1PEG8, PEG4, and PEG12 are as described in claim 78, Cn_diacid is -C(O)-(CH ２ ) ｎ－２ -COOH, where n is 10, 12, 14, 16, 18, or 22. A hepcidin analog according to any one of claims 1 to 77, or a pharmaceutically acceptable salt or solvate thereof.

80. The aforementioned peptide is given by formula XXII: R １ -Xbb1-Thr-His-B1-B2-Cys-Ile-B5(L1Z)-B6-B7(L1Z)-J-Y1-Y2-R ２ (XXII) This is due to, During the ceremony: L1, Z, J, Y1, and Y2 are as described in the claim; R １ However, hydrogen, C １ ~C ６ Alkyl, C ６ ~C １２ Ariel, C ６ ~C １２ Aryl-C １ ~C ６ Alkyl, C １ ~C ２０ Alkanoyl, C ２ ~C ２０ Alkenoyl, or C １ ~C ２０ It is a cycloalkanoyl; R ２ However, NH ２ or OH; Xbb1 is Glu, substituted Glu, isoGlu, (D)Glu, (D)isoGlu, bhGlu, or bGlu; Each of B1 and B6 is independently Phe, substituted Phe, Dpa, substituted Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, or 2Pal; B2 is Pro, substituted Pro, propanoic acid Pro, butanoic acid Pro, D-Pro, bhPro, D-bhPro, NPC, or D-NPC; B5 is Lys or (D)Lys; B7 is Lys or (D)Lys. A hepcidin analog according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

81. - Each L1Z is independent, -PEG11_OMe, -PEG12_C18 acid, -1PEG2_1PEG2_Ahx_Palm, -1PEG2_Ahx_Palm, -Ado_Palm, -Ahx_Palm, -Ahx_PEG20K, -PEG12_Ahx_IsoGlu_Behenic Acid, -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, During the ceremony: PEG11_OMe is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) １１ -OMe] and 1PEG2 is -C(O)-CH ２ - (OCH ２ CH ２ ) ２ -NH-, PEG4 is -C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) ４ -NH-, PEG8 is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) ８ -NH-, 1PEG8 is -[C(O)-CH ２ - (OCH ２ CH ２ ) ８ -NH-, PEG12 is -[C(O)-CH ２ -CH ２ - (OCH ２ CH ２ ) １２ -NH-, Ado is -[C(O)-(CH ２ ) １１ -NH]- Cn acid is -C(O)(CH ２ ) ｎ－２ -CH ３ And the C18 acid is -C(O)-(CH ２ ) １６ -Me, Palm is -C(O)-(CH ２ ) １４ -Me, IsoGlu is isoglutamic acid, IsoGlu_Palm, And, Ahx is -[C(O)-(CH ２ ) ５ -NH]- Cn_diacid is -C(O)-(CH ２ ) ｎ－２ -COOH, where n is 10, 12, 14, 16, 18, or 22. A hepcidin analog according to claim 80, or a pharmaceutically acceptable salt or solvate thereof.

82. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_isoGlu_C ｎ It is a diacid, and Lys(1PEG2_1PEG2_isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

83. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(1PEG2_1PEG2_isoGlu_C ｎ (Diacid) and (D)Lys(1PEG2_1PEG2_IsoGlu_C ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

84. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG8_isoGlu_C ｎ It is a diacid, and Lys(1PEG8_isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

85. Xaa1 (B5 (L1Z)) or Xaa2 (B7 (L1Z)) is (D)Lys(1PEG8_IsoGlu_C ｎ (Diacid) and (D)Lys(1PEG8_IsoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

86. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(1PEG2_1PEG2_Dap_C ｎ It is a diacid, and Lys(1PEG2_1PEG2_Dap_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

87. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(IsoGlu_C ｎ It is a diacid, and Lys(isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

88. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(IsoGlu_C ｎ (Diacid) and (D)Lys(IsoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

89. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_IsoGlu_C ｎ It is a diacid, and Lys(PEG12_isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

90. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_IsoGlu_C ｎ (Diacid) and (D)Lys(PEG12_IsoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

91. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_IsoGlu_C ｎ It is a diacid, and Lys(PEG4_isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

92. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_IsoGlu_C ｎ (Diacid) and (D)Lys(PEG4_IsoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

93. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG4_PEG4_IsoGlu_C ｎ It is a diacid, and Lys(PEG4_PEG4_isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

94. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG4_PEG4_IsoGlu_C ｎ (Diacid) and (D)Lys(PEG4_PEG4_IsoGlu_C ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

95. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(IsoGlu_C ｎ It is a diacid, and Lys(isoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

96. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(IsoGlu_C ｎ (Diacid) and (D)Lys(IsoGlu_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

97. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C ｎ (Diacid) and Lys(PEG12_Ahx_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

98. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_Ahx_C ｎ (Diacid) and Lys(PEG12_Ahx_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

99. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_Ahx_C ｎ (Diacid) and (D)Lys(PEG12_Ahx_C ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

100. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is Lys(PEG12_C ｎ (Diacid), and Lys(PEG12_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

101. Xaa1(B5(L1Z)) or Xaa2(B7(L1Z)) is (D)Lys(PEG12_C ｎ (Diacid) and (D)Lys(PEG12_C) ｎ (Diacid) A hepcidin analog according to any one of claims 1 to 81, wherein n is 10, 12, 14, 16, or 18.

102. A hepcidin analog according to any one of claims 1 to 102, wherein Xbb1 is Glu, (Me)Glu, (OMe)Glu, hGlu, or bhGlu, or a pharmaceutically acceptable salt or solvate thereof.

103. A hepcidin analog according to any one of claims 1 to 102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is isoAsp or Asp(OMe).

104. A hepcidin analog according to any one of claims 1 to 102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Gla or Glp.

105. A hepcidin analog according to any one of claims 1 to 102, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu.

106. A hepcidin analog according to any one of claims 1 to 102, wherein Xbb1 is Glu, Glu-OMe, isoGlu, (D)Glu, or (D)isoGlu, or a pharmaceutically acceptable salt or solvate thereof.

107. A hepcidin analog according to any one of claims 1 to 106, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa or Phe.

108. A hepcidin analog according to any one of claims 1 to 106, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa.

109. A hepcidin analog according to any one of claims 1 to 108, or a pharmaceutically acceptable salt or solvate thereof, wherein B2 is Pro, propanoic acid Pro, butanoic acid Pro, bhPro, or NPC.

110. A hepcidin analog according to any one of claims 1 to 108, or a pharmaceutically acceptable salt or solvate thereof, wherein B2 is Pro.

111. A hepcidin analog according to any one of claims 1 to 110, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe or Phe.

112. A hepcidin analog according to any one of claims 1 to 110, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe.

113. A hepcidin analog according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or solvate thereof, wherein B7 is Glu or absent.

114. A hepcidin analog according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or solvate thereof, wherein B7 is Glu.

115. A hepcidin analog according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or solvate thereof, wherein B7 is absent.

116. A hepcidin analog according to any one of claims 1 to 115, or a pharmaceutically acceptable salt or solvate thereof, wherein J is (D) Lys, MeLys, or Arg.

117. A hepcidin analog according to any one of claims 1 to 115, or a pharmaceutically acceptable salt or solvate thereof, wherein J is (D)Lys.

118. A hepcidin analog according to any one of claims 1 to 117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is Cys, (D)Cys, NMeCys, aMeCys, or Pen.

119. A hepcidin analog according to any one of claims 1 to 117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is Cys.

120. R ２ However, NH ２ The hepcidin analog described in any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof.

121. R ２ A hepcidin analog according to any one of claims 1 to 19, wherein the hepcidin is an OH group, or a pharmaceutically acceptable salt or solvate thereof.

122. A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The peptide is one of the peptides listed in Tables 2A to 2B, and the peptide is cyclized via a disulfide bond between two Cys molecules. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

123. It is a peptide, The peptide in question contains or consists of one of the peptides listed in Tables 2A to 2B. The peptide is cyclized via a disulfide bond between two Cys molecules. *The peptide in which Peg11 is Peg11-OMe.

124. A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The aforementioned peptide Compound ID number 12 Compound ID number 19 Compound ID number 107 Compound ID number 113 Compound ID number 256 Compound ID number 257 Compound ID number 280 Compound ID number 281 The hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

125. A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The aforementioned peptide Compound ID number 255 or Compound ID280 The hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

126. Formula LI: ( １ ................ B4-Xaa1-B6-Xaa2-J-Y1-Y2-R ２ () Xc A hepcidin analog containing a peptide, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony: R １ However, hydrogen, C １ ~C ６ Alkyl, C ６ ~C １２ Ariel, C ６ ~C １２ Aryl-C １ ~C ６ Alkyl, C １ ~C ２０ Alkanoyl, or C １ ~C ２０ It is a cycloalkanoyl; R ２ However, NH ２ or OH; Xbb1 is isoAsp, Asp(OMe), Glu, bhGlu, bGlu, Gla, or Glp; Xcc1 is any amino acid other than Thr, and Xdd1 is any amino acid, or Xcc1 is any amino acid, and Xdd1 is any amino acid other than His; Xaa1 is B5, i) B5 is nonexistent, Lys, D-Lys, or Lys(Ac), Xaa2 is B7(L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys, or ii) Xaa1 is B5 (L1Z), B5 is Lys, D-Lys, or Lys (Ac), Xaa2 is B7, B7 is either Glu or does not exist; Each of B1 and B6 is independently Phe, Dpa, bhPhe, a-MePhe, NMe-Phe, D-Phe, 2Pal, or Ala; B2 is Pro, D-Pro, bhPro, D-bhPro, NPC, D-NPC, Ala, MeAla, or Leu; B3 is Cys, homocys, (D)cys, a-Mecys, or Pen; B4 is Ile, Val, Leu, NLeu, Ala, or MeIle; L1 is absent, Dapa, D-Dapa, or isoGlu, PEG, Ahx, isoGlu-PEG, isoGlu-PEG, PEG-Ahx, isoGlu-Ahx, or isoGlu-PEG-Ahx. Ahx is the aminohexanoic acid portion, and PEG is -[C(O)-CH ２ - (Peg) ｎ -N(H)] ｍ -, or -[C(O)-CH ２ -CH ２ - (Peg) ｎ -N(H)] ｍ And Peg is -OCH ２ CH ２ -, where m is 1, 2, or 3, and n is an integer between 1 and 100K; Z is the half-life extension portion; J is either Lys, D-Lys, Arg, Pro, -Pro-Arg-, -Pro-Lys-, -Pro-(D)Lys-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (SEQ ID NO: 249), -Pro-Arg-Ser-Lys-Sar- (SEQ ID NO: 250), -Pro-Arg-Ser-Lys-Gly- (SEQ ID NO: 251), or J is any amino acid; Y1 is Cys, homocys, (D)cys, NMecys, aMecys, or Pen; Y2 is either an amino acid or absent; Dapa is diaminopropanoic acid, Dpa or DIP is 3,3-diphenylalanine or β,β-diphenylalanine, bhPhe is β-homophenylalanine, Bip is biphenylalanine, bhPro is β-homoproline, Tic is L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, NPC is L-nipecotinic acid, bhTrp is β-homotryptophan, 1-Naal is 1-naphthylalanine, 2-Naal is 2-naphthylalanine, Orn is ornithine, Nleu is norleucine, Abu is 2-aminobutyric acid, 2Pal is 2-pyridylalanine, and Pen is penicillamine; Substituting Phe is phenylalanine, where phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted bhPhe is β-homophenylalanine, and phenyl is substituted with F, Cl, Br, I, OH, methoxy, dimethoxy, dichloro, dimethyl, difluoro, pentafluoro, allyloxy, azide, nitro, 4-carbamoyl-2,6-dimethyl, trifluoromethoxy, trifluoromethyl, phenoxy, benzyloxy, carbamoyl, t-Bu, carboxyl, CN, or guanidine; The substituted trp is N-methyl-L-tryptophan, α-methyltryptophan, or tryptophan, which is substituted with F, Cl, OH, or t-Bu; The substituted bhTrp is N-methyl-L-b-homotryptophan, a-methyl-b-homotryptophan, or b-homotryptophan, which is substituted with F, Cl, OH, or t-Bu; Here: i) The peptide of formula I optionally contains one or more R １ , B1, B2, B3, B4, B5, B6, B7, J, Y1, Y2, or R2 are PEG-encoded; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

127. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is any amino acid other than Thr and Xdd1 is any amino acid.

128. The hepcidin analog according to claim 127, wherein Xdd1 is His.

129. Formula LII: ( １ ____________________________) B4-Xaa1-B6-Xaa2-J-Y1-Y2-R ２ (.) Contains peptides produced by During the ceremony: Xcc1 is any amino acid other than Thr, and R １ , R ２ Xaa1, Xbb1, B1 to B4, B6, J, Y1, and Y2 are as described in claim 126. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

130. A hepcidin analog according to claim 129, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab.

131. A hepcidin analog according to claim 129, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

132. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is any amino acid and Xdd1 is any amino acid other than His.

133. A hepcidin analog according to claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is Thr.

134. Formula LIII: 2 １ _____________________________________) B4-Xaa1-B6-Xaa2-J-Y1-Y2-R ２ ()) Contains peptides produced by During the ceremony: Xdd1 is any amino acid other than His, and R １ , R ２ Xaa1, Xbb1, B1 to B4, B6, J, Y1, and Y2 are as described in claim 126. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

135. A hepcidin analog according to claim 134, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substituted His.

136. A hepcidin analog according to claim 134, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

137. A hepcidin analog according to any one of claims 126 to 136, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5, and B5 is absent, Lys, or D-Lys, and Xaa2 is B7 (L1Z), and B7 is Lys, D-Lys, homoLys, or a-Me-Lys.

138. A hepcidin analog according to any one of claims 126 to 136, or a pharmaceutically acceptable salt or solvate thereof, wherein Xaa1 is B5 (L1Z), B5 is Lys or D-Lys, Xaa2 is B7, and B7 is Glu or absent.

139. Formula (LI-A1) or (LI-A2): R １ -Xbb1-Xcc1-His-B1-B2-B3-B4-B5-B6-B7(L1Z)-J-Y1-Y2-R ２ (LI-A1), or R １ -Xbb1-Thr-Xdd1-B1-B2-B3-B 4-B5-B6-B7(L1Z)-J-Y1-Y2-R ２ (LIMA2) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R １ , R ２ , B1 to B6, L1, Z, J, Y1, and Y2 are as described in claim 126; B7 is either Lys or D-Lys; Here: i) The peptide optionally contains one or more R １ PEG is encapsulated in B1, B2, B3, B4, B5, B6, J, Y1, Y2, or R2; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Ph, then B5 is not Lys; iv) If the peptide is a peptide dimer, then B7(L1Z)-J-Y1-Y2 is not present; v) If the peptide is a peptide dimer, the peptide dimer is a) Through the linker section, b) In one of the monomeric subunits, via an intermolecular disulfide bond between two B3 residues, or c) via both the linker moiety and the intermolecular disulfide bond between the two B3 residues, Dimerized, d) The linker portion includes a half-life extension portion, A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

140. Formula (LI-B1) or (LI-B2): R １ -Xbb1-Xcc1-His-B1-B2-B3-B4-B5(L1Z)-B6-B7-J-Y1-Y2-R ２ (LI-B1), or R １ -Xbb1-Thr-Xdd1-B1-B2-B3-B 4-B5(L1Z)-B6-B7-J-Y1-Y2-R ２ (LI-B2) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R １ , R ２ , B1 to B6, L1, Z, J, Y1, and Y2 are as described in claim 126; Here: i) The peptide optionally contains one or more R １ , B1, B2, B3, B4, B6, B7, J, Y1, Y2, or R2 are PEG-encoded; ii) The peptide is optionally cyclized via a disulfide bond between B3 and Y1; iii) If B6 is Phe, Y1 is Cys, and Y2 is Lys, then J is either Pro, Arg, Gly, -Pro-Arg-, -Pro-Arg-Ser-, -Pro-Arg-Ser-Lys- (sequence number 249) or does not exist. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

141. A hepcidin analog according to any one of claims 126 to 140, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is F, Dpa, BIP, or bhPhe, B2 is Pro, NCP, (D)Pro, or (D)NCP, B3 is Cys, a-MeCys, or homoCys, B4 is Ile, B5 is Lys, or (D)Lys, B6 is Phe, substituted Phe, bhPhe, or 2Pal, and B7 is Lys, or (D)Lys.

142. A hepcidin analog according to any one of claims 126 to 140, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is Dpa.

143. A hepcidin analog according to any one of claims 126 to 142, or a pharmaceutically acceptable salt or solvate thereof, wherein B2 is Pro.

144. A hepcidin analog according to any one of claims 126 to 143, or a pharmaceutically acceptable salt or solvate thereof, wherein B3 is Cys.

145. A hepcidin analog according to any one of claims 126 to 144, or a pharmaceutically acceptable salt or solvate thereof, wherein B4 is Ile.

146. A hepcidin analog according to any one of claims 126 to 145, or a pharmaceutically acceptable salt or solvate thereof, wherein B5 is (D) Lys.

147. A hepcidin analog according to any one of claims 126 to 146, wherein B5 is Lys(Ac), or a pharmaceutically acceptable salt or solvate thereof.

148. A hepcidin analog according to any one of claims 126 to 147, or a pharmaceutically acceptable salt or solvate thereof, wherein B6 is bhPhe.

149. B7(L1Z) is -N(H)C[CH ２ (CH ２ CH ２ CH ２ ) ｍ A hepcidin analog according to any one of claims 126 to 148, wherein N(H)L1Z](H)-C(O)- and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof.

150. B7(L1Z) is -N(H)C[CH ２ A hepcidin analog according to any one of claims 126 to 149, wherein the compound is N(H)L1Z](H)-C(O)-.

151. B7(L1Z) is -N(H)C[CH ２ CH ２ CH ２ CH ２ A hepcidin analog according to any one of claims 126 to 149, wherein the compound is N(H)L1Z](H)-C(O)-, or a pharmaceutically acceptable salt or solvate thereof.

152. Formula LIV or LV: R １ -Xbb1-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (LIV), or ( １ ____________________________________________ _______________________________________________ ２ ヨ ２ ヨ ２ ヨ ２ (())___________________________________________________ ２ (()) Contains peptides produced by During the ceremony: Xbb1, Xcc1, Xdd1, R １ , R ２ L1, Z, J, Y1, and Y2 are as set forth in claim 126. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

153. A hepcidin analog according to any one of claims 126 to 152, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu, hGlu, or bhGlu.

154. A hepcidin analog according to any one of claims 126 to 152, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is isoAsp or Asp(OMe).

155. A hepcidin analog according to any one of claims 126 to 152, or a pharmaceutically acceptable salt or solvate thereof, wherein Xbb1 is Glu.

156. Formula LVI or LVII: R １ -Glu-Xcc1-His-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (LVI), or R １ -Glu-Thr-Xdd1-[Dpa]-Pro-Cys-Ile-[(D)Lys]-bhPhe-N(H)C[CH ２ CH ２ CH ２ CH ２ N(H)L1Z](H)-C(O)-J-Y1-Y2-R ２ (LVII) Contains peptides produced by During the ceremony: Xcc1, Xdd1, R １ , R ２ L1, Z, J, Y1, and Y2 are as set forth in claim 126. A hepcidin analog according to claim 126, or a pharmaceutically acceptable salt or solvate thereof.

157. A hepcidin analog according to any one of claims 126 to 156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, Ala, Leu, Hyp, Dap, (D)Asp, or Dab.

158. A hepcidin analog according to any one of claims 126 to 156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is a substituted Thr, Ser, (D)Ser, or Ala.

159. A hepcidin analog according to any one of claims 126 to 156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xcc1 is Ser, (D)Ser, or Ala.

160. A hepcidin analog according to any one of claims 126 to 156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, Leu, Dap, Orn, 3Quin, or substituted His.

161. A hepcidin analog according to any one of claims 126 to 156, or a pharmaceutically acceptable salt or solvate thereof, wherein Xdd1 is 2Pal, 3Pal, Dab, Ala, or Leu.

162. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein -J-Y1-Y2- is -Cys-, -Pro-Cys-, -Lys-Cys-, -(D)Lys-Cys-, -Arg-Cys-, -Dap-Cys-, -Cys-(D)Lys-, -Dap-hCys-, -Pro-Arg-Cys-, -Pro-Arg-Ser-Cys- (SEQ ID NO: 253), -Pro-Arg-Ser-Lys-Cys- (SEQ ID NO: 254), or -Pro-Arg-Ser-Lys-Sar-Cys- (SEQ ID NO: 255).

163. A hepcidin analog according to any one of claims 126 to 161, wherein -J-Y1-Y2- is -Arg-Cys-, -(D)Lys-Cys-, or -Lys-Cys-, or a pharmaceutically acceptable salt or solvate thereof.

164. A hepcidin analog according to any one of claims 126 to 161, wherein -J-Y1-Y2- is -(D)Lys-Cys, or a pharmaceutically acceptable salt or solvate thereof.

165. A hepcidin analog according to any one of claims 126 to 161, wherein -J-Y1-Y2- is -Arg-Cys, or a pharmaceutically acceptable salt or solvate thereof.

166. A hepcidin analog according to any one of claims 126 to 161, wherein L1 is a single bond, or a pharmaceutically acceptable salt or solvate thereof.

167. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu.

168. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is Ahx.

169. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-Ahx.

170. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG.

171. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is PEG-Ahx.

172. A hepcidin analog according to any one of claims 126 to 161, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is iso-Glu-PEG-Ahx.

173. A hepcidin analog according to any one of claims 126 to 172, or a pharmaceutically acceptable salt or solvate thereof, wherein PEG is -[C(O)-CH2-(PEG)n-N(H)]m- or -[C(O)-CH2-CH2-(PEG)n-N(H)]m-, PEG is -OCH2CH2-, m is 1, 2, or 3, and n is an integer from 1 to 100, or 10K, 20K, or 30K.

174. A hepcidin analog according to any one of claims 126 to 173, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

175. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

176. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

177. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.

178. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 8.

179. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 11.

180. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 12.

181. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 20 K.

182. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 1PEG2, and 1PEG2 is -C(O)-CH2-(PEG)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

183. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 2PEG2, and 2PEG2 is -C(O)-CH2-CH2-(PEG)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

184. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 1Peg2-1Peg2, and each 1Peg2 is -C(O)-CH2-CH2-(Peg)2-N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

185. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 1Peg2-1Peg2, and 1Peg2-1Peg2 is -[(C(O)-CH2-(OCH2CH2)2-NH-C(O)-CH2-(OCH2CH2)2-NH-]-, or a pharmaceutically acceptable salt or solvate thereof.

186. A hepcidine analog according to any one of claims 126 to 174, wherein PEG is 2PEG4, and 2PEG4 is -C(O)-CH2-CH2-(PEG)4-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)4-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

187. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 1PEG8, and 1PEG8 is -C(O)-CH2-(PEG)8-N(H)-, or -[C(O)-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

188. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 2PEG8, and 2PEG8 is -C(O)-CH2-CH2-(PEG)8-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)8-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

189. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 1PEG11, and 1PEG11 is -C(O)-CH2-(PEG)11-N(H)-, or -[C(O)-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

190. A hepcidin analog according to any one of claims 126 to 174, wherein PEG is 2PEG11, and 2PEG11 is -C(O)-CH2-CH2-(PEG)11-N(H)-, or -[C(O)-CH2-CH2-(OCH2CH2)11-NH]-, or a pharmaceutically acceptable salt or solvate thereof.

191. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, 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]-.

192. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Lys, the -C(O)- of PEG is bound to the Ne of Lys.

193. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to isoGlu, the -N(H)- of PEG is bound to the -C(O)- of isoGlu.

194. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Ahx, the -N(H)- of PEG is bound to the -C(O)- of Ahx.

195. A hepcidin analog according to any one of claims 126 to 174, or a pharmaceutically acceptable salt or solvate thereof, wherein when PEG is bound to Palm, the -N(H)- of PEG is bound to the -C(O)- of Palm.

196. A hepcidin analog according to any one of claims 126 to 195, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Palm.

197. R ２ However, NH ２ The hepcidin analog described in any one of claims 126 to 196, or a pharmaceutically acceptable salt or solvate thereof.

198. R ２ A hepcidin analog according to any one of claims 126 to 196, or a pharmaceutically acceptable salt or solvate thereof, wherein the hepcidin analog is an OH group.

199. R １ However, C １ ~C ２０ A hepcidin analog according to any one of claims 126 to 196, which is an alkanoyl, or a pharmaceutically acceptable salt or solvate thereof.

200. R １ However, the hepcidin analog according to any one of claims 126 to 196, which is isovaleric acid, or a pharmaceutically acceptable salt or solvate thereof.

201. A hepcidin analog containing or comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof, The peptide is one of the peptides listed in Table 2, or a dimer thereof. The peptide is cyclized via a disulfide bond between two Cys molecules. The aforementioned hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof.

202. Peptides, or pharmaceutically acceptable salts or solvates thereof, The peptide in question contains or consists of one of the peptides listed in Table 2. The peptide is cyclized via a disulfide bond between two Cys molecules. * indicates that Peg11 is Peg11-OMe. The peptide, or a pharmaceutically acceptable salt or solvate thereof.

203. A polynucleotide encoding the peptide according to any one of claims 1 to 202.

204. A vector comprising the polynucleotide described in claim 203.

205. A hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or a peptide, according to any one of claims 1 to 202, A pharmaceutically acceptable carrier, excipient, or vehicle A pharmaceutical composition containing the above.

206. A method for binding to ferroportin or inducing the internalization and degradation of ferroportin, The method comprising contacting the ferroportin with at least one hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or a peptide, as described in any one of claims 1 to 202.

207. A method for treating iron metabolism disorders in those who require it, The method comprising providing to the subject an effective amount of a hepcidin analog according to any one of claims 1 to 202, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 205.

208. A method for treating a disease or disorder related to dysregulated hepcidin signaling in a person in need thereof, The method comprising providing to the subject an effective amount of a hepcidin analog according to any one of claims 1 to 202, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 205.

209. The method according to claim 207 or 208, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, spray, sublingual, buccal, parenteral, rectal, vaginal, or topical route of administration.

210. The method according to claim 209, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration.

211. The method according to any one of claims 207 to 210, wherein the disease or disorder is a disease or iron metabolism.

212. The method according to claim 211, wherein the iron metabolic disorder is an iron overload disorder.

213. The method according to any one of claims 207 to 210, wherein the disease or disorder is hemochromatosis, thalassemia, or polycythemia.

214. The method according to any one of claims 207 to 213, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject up to twice a day, up to once a day, up to once every two days, up to once a week, or up to once a month.

215. The method according to any one of claims 207 to 214, wherein the hepcidin analog, or a pharmaceutically acceptable salt or solvate thereof, is provided to the subject in a dose of about 1 mg to about 100 mg.

216. A device comprising a hepcidin analog according to any one of claims 1 to 202, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 205, for the delivery of the hepcidin analog or a pharmaceutically acceptable salt or solvate thereof to a subject, optionally by oral or subcutaneous means.

217. A kit comprising a hepcidin analog according to any one of claims 1 to 202, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 205, packaged together with a reagent, device, or instructions, or a combination thereof.

218. Contains or consists of a peptide, wherein the peptide is: hepcidin analogs, or pharmaceutically acceptable salts or solvates thereof.

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