Hepcidin mimetics for the treatment of sickle cell disease

Abstract

The present disclosure provides compositions and methods for the treatment and / or prevention of sickle cell disease.

Description

【Technical Field】 【0001】 Cross - Reference to Related Applications This application claims priority based on U.S. Provisional Application No. 63 / 349,908, filed on June 7, 2022, which is hereby incorporated by reference in its entirety for all purposes. 【0002】 Description of the Sequence Listing The Sequence Listing XML related to this application is provided in XML file format and is hereby incorporated by reference into this specification. The name of the XML file containing the Sequence Listing XML is PRTH_080_01WO_ST26.xml. The XML file is 114,337 bytes, was created on June 5, 2023, and was electronically filed via the USPTO Patent Center. 【0003】 The present disclosure relates, inter alia, to compositions and methods for the treatment and / or prevention of sickle cell disease. 【Background Art】 【0004】 Sickle cell disease (SCD) is a group of hereditary blood disorders. SCD is characterized by abnormal hemoglobin, which results in red blood cells that take on a distorted, rigid sickle shape. Healthy red blood cells are round and they move through small blood vessels to carry oxygen to all parts of the body. Sickle - shaped red blood cells tend to cause intravascular hemolysis and intermittent blood flow obstruction. When these sickle cells pass through small blood vessels, they clog and impede blood flow. This can lead to severe pain, and episodes of organ ischemia - reperfusion injury, such as kidney failure, liver conditions, stroke, infections due to splenic infarction, as well as other complications. 【0005】 Various forms of SCD include homozygous sickle cell anemia (HbSS), heterozygous sickle cell trait (HbAC), and hemoglobin SC disease (HbSC), sickle cell hemoglobin D (HbSD), sickle cell hemoglobin E (HbSE), sickle cell hemoglobin O (HbSO), sickle cell-beta-plus-thalassemia (HbSβ + thalassemia), sickle cell-beta-zero-thalassemia (HbSβ0 thalassemia). 【0006】 Currently, there is a large unmet medical need for safe and effective therapies for the treatment of sickle cell disease and its complications. This disclosure meets this need and other needs. 【Summary of the Invention】 【0007】 This disclosure relates to the use of hepcidin mimetics or peptides for treating sickle cell disease. 【0008】 In one aspect, this disclosure provides a method of treating sickle cell disease in a subject, the method comprising administering to the subject an effective amount of a hepcidin mimetic disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a hepcidin mimetic disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a hepcidin mimetic or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. In some embodiments, the hepcidin mimetic is a peptide. Subtypes or genotypes of sickle cell disease that can be treated with the hepcidin mimetics disclosed herein include, but are not limited to, sickle cell anemia (HbSS), HbSβ0 thalassemia, HbSβ+ thalassemia, and hemoglobin SC disease (HbSC). 【0009】 In some embodiments, this disclosure provides a method of treating sickle cell disease or a subtype or genotype of sickle cell disease in a subject, the method comprising administering to the subject an effective amount of formula (I): R1-X-Y-R2 (I) 〔Wherein, R1 is hydrogen, C1-C6 alkyl, C6-C12 aryl, C1-C20 alkanoyl, or pGlu; R2 is NH2 or OH; X is the amino acid sequence of formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (II) (wherein, X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp, or absent; X2 is Thr, Ala, or D-Thr; X3 is His, Lys, D-His, or Lys; X4 is Phe, Ala, Dpa, or D-Phe; X5 is Pro, Gly, Arg, Lys, Ala, D-Pro, or bhPro; X6 is Ile, Cys, Arg, Lys, D-Ile, or D-Cys; X7 is Cys, Ile, Leu, Val, Phe, D-Ile, or D-Cys; X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu, or D-Ile; X9 is Phe or bhPhe; X10 is Lys, Phe, or absent) ; When Y is absent, X7 is Ile; Y is the amino acid sequence of formula III: Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (III) (wherein, Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser, or absent; Y2 is Pro, Ala, Cys, Gly, or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp, or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr, or absent; Y5 is Lys, Met, Arg, Ala, or absent; Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val, or absent; Y7 is Trp, Lys, Gly, Ala, Ile, Val, or absent; Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg, or absent; Y9 is Cys, Tyr, or absent; Y10 is Met, Lys, Arg, Tyr, or absent; Y11 is Arg, Met, Cys, Lys, or absent; Y12 is Arg, Lys, Ala, or absent; Y13 is Arg, Cys, Lys, Val, or absent; Y14 is Arg, Lys, Pro, Cys, Thr, or absent; Y15 is Thr, Arg, or absent) is]] administering a hepcidin mimetic peptide comprising or having the same, or a pharmaceutically acceptable salt or solvate thereof; the peptide of formula I is optionally pegylated at R1, X or Y; the side chains of the amino acids of the peptide are optionally conjugated to a lipophilic substituent or a polymeric moiety; the peptide of formula I optionally has a disulfide bond formed between the thiol groups of two cysteine residues; Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid, bhPro is β-homoproline, Provide the method. In some embodiments of the compound of formula (I), a disulfide bond is formed between the thiol groups of two cysteine residues. In one embodiment, the hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered subcutaneously. 【0010】 In some embodiments, the hepcidin mimetic comprises, or consists of, any one of the peptides of Formulas I - VIII disclosed herein. In certain embodiments, the peptide has the following sequence or structure: Isovaleric acid - DTHFPICIFGPRSKGWVC - NH2 (Compound 1; SEQ ID NO: 1)); Isovaleric acid - DTHFPCIIFGPRSKGWVCK - NH2 (Compound 2; SEQ ID NO: 2); Isovaleric acid - DTHFPCIIFEPRSKGWVCK - NH2 (Compound 3; SEQ ID NO: 3); Isovaleric acid - DTHFPCIIFGPRSKGWACK - NH2 (Compound 4; SEQ ID NO: 4); Isovaleric acid - DTHFPCIIFGPRSKGWVCKK - NH2 (Compound 5; SEQ ID NO: 5); Isovaleric acid - DTHFPCIIFVCHRPKGCYRRVCR - NH2 (Compound 6; SEQ ID NO: 6); Isovaleric acid - DTHFPCI(K(PEG8))FGPRSKGWVCK - NH2 (Compound 7; SEQ ID NO: 7); Isovaleric acid - DTHFPCIKF(K(PEG8))PRSKGWVCK - NH2 (Compound 8; SEQ ID NO: 8); Isovaleric acid - DTHFPICIFGPRS(K(PEG8))GWVC - NH2 (Compound 9; SEQ ID NO: 9); Isovaleric acid - DTHFPICIFGPRS(K(PEG4))GWVC - NH2 (Compound 10; SEQ ID NO: 10); Isovaleric acid - DTHFPCIIFGPRSRGWVC(K(PEG8)) - NH2 (Compound 11; SEQ ID NO: 11); Isovaleric acid - DTHFPCIIFGPRSRGWVC(K(PEG4)) - NH2 (Compound 12; SEQ ID NO: 12); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2 (Compound 13; SEQ ID NO: 13); Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2 (Compound 14; SEQ ID NO: 14); Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2 (Compound 15; SEQ ID NO: 15); Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2 (Compound 16; SEQ ID NO: 16); Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2 (Compound 17; SEQ ID NO: 17); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))NH2 (Compound 18; SEQ ID NO: 18); Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH2 (Compound 19; SEQ ID NO: 19); Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH2 (Compound 20; SEQ ID NO: 20); Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH2 (Compound 21; SEQ ID NO: 21); Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH2 (Compound 22; SEQ ID NO: 22); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH2 (Compound 23; SEQ ID NO: 23); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2 (Compound 24; SEQ ID NO: 24); Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH2 (Compound 25; SEQ ID NO: 25); Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-NH2 (Compound 26; SEQ ID NO: 26); Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH2 (Compound 27; SEQ ID NO: 27); Isoleucine-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-NH2 (Compound 28; SEQ ID NO: 28); Isoleucine-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH2 (Compound 29; SEQ ID NO: 29); Isoleucine-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-NH2 (Compound 30; SEQ ID NO: 30); Isoleucine-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-NH2 (Compound 31; SEQ ID NO: 31); Isoleucine-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2 (Compound 32; SEQ ID NO: 32); Isoleucine-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2 (Compound 33; SEQ ID NO: 33); Isoleucine-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2 (Compound 34; SEQ ID NO: 34); Isoleucine-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2 (Compound 35; SEQ ID NO: 35); Isoleucine-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2 (Compound 36; SEQ ID NO: 36); Isoleucine-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-NH2 (Compound 37; SEQ ID NO: 37); Isoleucine-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2 (Compound 38; SEQ ID NO: 38); Isoleucine-DTHFPCIKF(K(PEG11-Palm))PRSK[Sar]CK-NH2 (Compound 39; SEQ ID NO: 39); Isoleucine-DTHFPCIKF-NH2 (Compound 40; SEQ ID NO: 40); Hy-DTHFPCIKF-NH2 (Compound 41; SEQ ID NO: 41); Isoleucine-DTHFPCIIF-NH2 (Compound 42; SEQ ID NO: 42); Hy-DTHFPCIIKF-NH2 (Compound 43; SEQ ID NO: 43); Iso-Val-DTKFPCIIF-NH2 (Compound 44; SEQ ID NO: 44); Hy-DTKFPCIIF-NH2 (Compound 45; SEQ ID NO: 45); or Iso-Val-ETHFPCI(K(IsoGlu_Palm))FEPRSKGCK-NH2 (Compound 46; SEQ ID NO: 46) comprises or consists of one of the foregoing, and in each of Compounds 1-40 and 46, the thiol groups of the two cysteine residues are optionally joined together to form a disulfide bond. BRIEF DESCRIPTION OF THE DRAWINGS 【0011】 【Figure 1】 A and B provide graphs showing that Compound 46 decreases spleen size in Townes SCD mice. A: Spleen weight. B: Spleen-to-body weight ratio. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6-10 mice per group. 【Figure 2】 A and B provide graphs showing that Compound 46 decreases liver size in Townes SCD mice. A: Liver weight. B: Liver-to-body weight ratio. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6-10 mice per group. 【Figure 3】A and B provide graphs showing red blood cells (RBC) and hemoglobin (HGB) induced in Townes mice treated with compound 46 or vehicle for 4 weeks. A: RBC. B: Hemoglobin. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 4】 A and B provide graphs showing the reticulocyte counts in Townes mice treated with compound 46 or vehicle for 4 weeks. A: Change in absolute reticulocyte count. B: Rate of change in reticulocytes. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 5】 A and B provide graphs showing the changes in hematocrit (HCT) and mean corpuscular volume (MCV) in Townes mice treated with compound 46 or vehicle for 4 weeks. A: Change in HCT expressed as a percentage. B: Change in MCV expressed as a volume. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 6】A and B provide graphs showing changes in mean corpuscular hemoglobin (MCH), hematocrit (HCT), and mean corpuscular hemoglobin concentration (MCHC) in Townes mice treated with compound 46 or vehicle for 4 weeks. A: Change in MCH expressed as mass. B: Change in MCHC expressed as concentration. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 7】 A and B provide graphs showing that compound 46 reduced the elevated white blood cell (WBC) count and lymphocyte count in Townes SCD mice. A: Change in WBC count. B: Change in lymphocyte count. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 8】 A and B provide graphs showing that compound 46 reduced the elevated neutrophil count and monocyte count in Townes SCD mice. A: Change in neutrophil count. B: Change in monocyte count. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Figure 9】A and B provide graphs showing the effects of compound 46 on total bilirubin and lactate dehydrogenase (LDH), which are red blood cell (RBC) hemolysis biomarkers in serum from Townes mice. A: Total bilirubin. B: LDH. Individual values, and mean ± standard deviation are shown, and statistical analysis was performed by comparing all treatment groups to the HbSS vehicle group using one-way ANOVA with Dunnett's multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 6 - 10 mice per group. 【Modes for Carrying Out the Invention】 【0012】 The present disclosure relates to compounds, compositions, and methods for treating sickle cell disease. In some embodiments, the present disclosure provides methods for treating sickle cell disease using a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. 【0013】 Definitions and Terminology Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In general, the terminology and techniques related 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. 【0014】 As used herein, the following terms shall have the meanings given to them unless otherwise specified. 【0015】 Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising", are to be understood to imply the inclusion of the stated integer (or component) or group of integers (or components), but not to imply the exclusion of any other integer (or component) or group of integers (or components). 【0016】 The singular forms "a", "an", and "the" include the plural forms unless the context clearly dictates otherwise. 【0017】 "About", when referring to a value, includes the stated value + / - 10% of the stated value. For example, about 50% includes the range of 45% to 55%, while about 20 molar equivalents includes the range of 18 to 22 molar equivalents, and about 10 mg includes the range of 9 mg to 11 mg. Thus, when referring to a range, "about" refers to each of the stated values + / - 10% of the stated value for each endpoint of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3. 【0018】 The term "including" is used in the sense of "including but not limited to". "Including" and "including but not limited to" are used interchangeably. 【0019】 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, livestock (e.g., cows, 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, livestock, etc. 【0020】 As used herein, the term "peptide" broadly refers to a sequence of two or more amino acids joined by peptide bonds. It should be understood that this term does not imply a specific length of the amino acid polymer, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring. 【0021】 As used herein, the term "hepcidin mimetic" broadly refers to peptide monomers and peptide dimers that contain one or more structural features and / or functional activities common to hepcidin or its functional regions. In certain embodiments, a hepcidin mimetic includes a peptide that shares a significant amino acid sequence identity with hepcidin, for example, a peptide that contains one or more amino acid insertions, deletions, or substitutions compared to the wild-type hepcidin, for example, the human hepcidin amino acid sequence. In certain embodiments, a hepcidin mimetic includes one or more additional modifications, such as conjugation to another compound. The term "hepcidin mimetic" encompasses any peptide monomer or peptide dimer disclosed herein. In some embodiments, a hepcidin mimetic has one or more functional activities of hepcidin. 【0022】 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), non-natural amino acids, modified amino acids, and amino acids not found in nature. It includes both D- and L-amino acids. Naturally occurring amino acids include those found in nature, such as the 23 amino acids that combine to form the building blocks of countless proteins in peptide chains. These are mainly L-stereoisomers, although a small number of D-amino acids are present in bacterial envelopes and some antibiotics. "Non-standard" naturally occurring amino acids are pyrrolysine (found in methanogens and other eukaryotes), selenocysteine (present in many prokaryotes and most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Non-natural" or "unnatural" amino acids are amino acids that are not proteinogenic (i.e., not encoded by the genetic code or not found in nature), whether occurring naturally or chemically synthesized. Over 140 naturally occurring amino acids are known, and thousands of combinations are possible. Examples of "non-natural" amino acids include β-amino acids (β 3 and β 2 ), homoamino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, and N-methyl amino acids. Non-natural or unnatural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to contain one or more groups or chemical moieties not naturally present on the amino acid. 【0023】 It will be apparent to those skilled in the art that the peptide sequences disclosed herein are shown arranged from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. A sequence in which the "Hy-" moiety is incorporated at the amino terminus (N-terminus) of the sequence and either the "-OH" moiety or the "-NH2" moiety is incorporated at the carboxy terminus (C-terminus) of the sequence is one of the sequences disclosed herein. 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, while the "-OH" or "-NH2" moiety at the C-terminus of the sequence represents a hydroxy 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 "-OH" moiety at the C-terminus may be used instead of the "-NH2" moiety at the C-terminus, and vice versa. Furthermore, it will be understood that, particularly in the situation where the amino terminus or carboxy terminus is linked to a linker or another chemical moiety (e.g., a PEG moiety), the moiety at the amino terminus or carboxy terminus may be linked, for example, by a covalent bond. 【0024】 The term "NH2" as used herein refers to a free amino group present at the amino terminus of a polypeptide. The term "OH" as used herein refers to a free carboxy group present at the carboxy terminus of a peptide. Furthermore, the term "Ac" as used herein refers to acetyl protection by acylation of the C-terminus or N-terminus of a polypeptide. 【0025】 The term "carboxy" as used herein refers to -CO2H. 【0026】 Most of the names of naturally occurring and non-naturally occurring aminoacyl residues used in this specification follow the nomenclature rules 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). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from such proposals, they shall be made clear to the reader. In Table 1A below, several abbreviations useful in explaining the present invention are defined as follows. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【0027】 Throughout this specification, unless a naturally occurring amino acid is referred to by its formal name (e.g., alanine, arginine, etc.), it is represented by its conventional three-letter or one-letter abbreviation (e.g., Ala or A for alanine, Arg or R for arginine, etc.). In the case of less common or non-naturally occurring amino acids, unless it is referred to by its formal name (e.g., sarcosine, ornithine, etc.), for its residues, commonly used three-letter or four-letter codes are adopted, such as Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Daba (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), pGlu (pyroglutamic acid), Gaba (γ-aminobutyric 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). 【0028】 Furthermore, R1 may be substituted with isovaleric acid or an equivalent in any sequence. In some embodiments where the peptide of the present invention is conjugated to an acidic compound, such as isovaleric acid, isobutyric acid, valeric acid, etc., reference to the presence of such conjugation is made in the form of the acid. Therefore, without being limited in any way, for example, instead of referring to isovaleryl to represent the conjugation of isovaleric acid with the peptide, in some embodiments of this application, such conjugation may be referred to as isovaleric acid. 【0029】 As used herein, the term "L-amino acid" refers to the "L" isomeric form of a peptide, and conversely, the term "D-amino acid" refers to the "D" isomeric form of a peptide. In certain embodiments, the amino acid residues described herein are in the "L" isomeric form, but residues in the "D" isomeric form may be used in place of any L-amino acid residue as long as the desired function is retained by the peptide. 【0030】 Unless otherwise specified, references are made to the L-isomeric forms of natural and non-natural amino acids having a chiral center. When appropriate, the D-isomeric forms of amino acids are represented in a conventional manner by the prefix "D" before the conventional three-letter code (e.g., Dasp, (D)Asp, or D-Asp; Dphe, (D)Phe, or D-Phe). 【0031】 As used herein, the term "dimer" broadly refers to a peptide comprising two or more monomeric subunits. Certain dimers include two DRPs. The dimers of the present invention include homodimers and heterodimers. The monomeric subunits of the dimer may be linked at their C-terminus or N-terminus, or via internal amino acid residues. The monomeric subunits of the dimer may be linked via the same site, or each may be linked via a different site (e.g., C-terminus, N-terminus, or internal site). 【0032】 As used herein, in the context of the specific peptide sequences disclosed herein, parentheses, e.g., (__), represent side-chain conjugation, and square brackets, e.g., [__], represent non-natural amino acid substitutions or amino acids, and conjugated side chains. Usually, when a linker is shown at the N-terminus of a peptide sequence, it represents that the peptide is dimerized with another peptide and the linker is attached to the N-terminus of the two peptides. Usually, when a linker is shown at the C-terminus of a peptide sequence or structure, it represents that the peptide is dimerized with another peptide and the linker is attached to the C-terminus of the two peptides. 【0033】 The term "cyclized", as used herein, refers to a reaction in which a portion of a polypeptide molecule is linked to another portion of the polypeptide molecule to form a closed ring, for example, by forming a disulfide bridge or other similar bond. 【0034】 The term "subunit", as used herein, refers to one of a pair of polypeptide monomers that are joined together to form a dimeric peptide composition. 【0035】 The term "linker moiety", as used herein, broadly refers to a chemical structure having the ability to link or join two peptide monomer subunits together to form a dimer. 【0036】 In the context of the present invention, the term "solvate" refers to a defined stoichiometric complex formed between a solute (e.g., a hepcidin mimetic according to the present invention or a pharmaceutically acceptable salt thereof) and a solvent. The solvent in this context can be, for example, water, ethanol, or another pharmaceutically acceptable, typically small molecule organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is commonly called a hydrate. 【0037】 The term "pharmaceutically acceptable salt", as used herein, refers to salts or zwitterionic forms of the peptides or compounds of the present invention that are soluble or dispersible in water or oil, suitable for treating diseases without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for the intended use. The salts can be prepared during the final isolation and purification of the compound or separately by reacting the amino group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate (isethionate), lactate, maleate, mesitylene sulfonate, methanesulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluene sulfonate, and undecanoate. Also, the amino groups in the compounds of the present invention may 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; benzyl and phenethyl bromides. 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, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. The pharmaceutically acceptable salts can preferably be salts selected, for example, from among 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 ions of the type N(R1)(R2)(R3)(R4)+, wherein R1, R2, R3 and R4 each independently typically represent hydrogen, optionally substituted C1-6-alkyl, or optionally substituted C2-6-alkenyl. Examples of suitable C1-6-alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C2-6-alkenyl groups that may be suitable 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 its latest editions), “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66:2 (1977). Also, for a review of suitable salts, see 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. Representative 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 and hemicalcium salts, may be formed. 【0038】 The term "alkyl" includes straight-chain or branched acyclic or cyclic saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. On the other hand, representative saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. On the other hand, representative unsaturated cyclic alkyls include, but are not limited to, cyclopentenyl, cyclohexenyl, etc. 【0039】 The term "thio", "mercapto", or "sulfanyl" means the -SH group. 【0040】 As used herein, the "therapeutically effective amount" of the peptide agonist of the present invention is intended to represent an amount of the peptide agonist sufficient to treat hepcidin-related diseases (e.g., diseases of iron metabolism), including but not limited to any of the diseases and disorders described herein. In certain embodiments, the therapeutically effective amount results in a desired benefit / risk ratio that is applicable to any medical treatment. 【0041】 Therapeutic method using hepcidin mimics Sickle cell disease (SCD) is a fairly common autosomal recessive disorder (approximately 1 in 500 people). The conversion of A to T at the sixth codon of the human β-globin gene results in HbS (α2β s2) Change the polar glutamic acid residues to nonpolar valine in the β-globin chains on the surface of the tetramer. The interaction between tetramers leads to the formation of HbS polymers / fibers, which causes the RBCs to become rigid and non-deformable, blocking small capillaries. Vascular occlusion events can cause severe tissue damage that can lead to stroke, splenic infarction, renal failure, liver and lung disorders, pain crises, and other complications. The sickling of red blood cells makes the cells fragile and causes chronic anemia by lysis. Treatments available to manage the symptoms include analgesics for pain management; hydroxyurea (which enlarges the size of RBCs to prevent sickling); blood transfusions (which can lead to transfusion iron overload); bone marrow / stem cell transplantation; and experimental therapies. 【0042】 Hepcidin targets ferroportin, the major iron transporter, causing its internalization and subsequent degradation. The regulation of hepcidin is extremely important in providing sufficient iron required for cellular function while also preventing iron toxicity. 【0043】 The present disclosure provides a method of treating SCD in a subject by administering a hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a composition containing a hepcidin mimetic or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. In certain embodiments, treatment with a hepcidin mimetic is beneficial in improving disease-related complete blood count (CBC) parameters, such as total white blood cells (WBC), total red blood cells (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), etc., and serum biomarkers, and controlling tissue damage in SCD. 【0044】 The various forms of SCD that can be treated using the hepcidin mimetic, or a pharmaceutically acceptable salt thereof, described or disclosed herein, or the compositions described herein, include homozygous sickle cell anemia (HbSS), heterozygous sickle cell trait (HbAC), compound heterozygous sickle cell hemoglobin C, sickle cell hemoglobin D (HbSD), sickle cell hemoglobin E (HbSE), sickle cell hemoglobin O (HbSO), sickle cell-beta-plus-thalassemia (HbSβ + thalassemia), sickle cell-beta-zero-thalassemia (HbSβ0 thalassemia). 【0045】 In some embodiments, the present disclosure provides a method of treating a subtype or genotype of sickle cell disease selected from sickle cell anemia (HbSS), HbSβ0 thalassemia, HbSβ+ thalassemia, or hemoglobin SC disease (HbSC). The method includes administering to a subject in need thereof an effective amount of a hepcidin mimetic or a pharmaceutically acceptable salt thereof, described or disclosed herein, or a composition containing a hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a composition comprising a hepcidin mimetic or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. In certain embodiments, the disease that can be treated using the methods described herein is HbSC. 【0046】 In some embodiments, the present disclosure provides a method of treating sickle cell anemia (SS), sickle cell hemoglobin C disease (SC), sickle cell beta plus thalassemia, or sickle cell beta zero thalassemia in a subject. The method includes administering to a subject in need thereof an effective amount of a hepcidin mimetic or a pharmaceutically acceptable salt thereof, described or disclosed herein, or a composition containing a hepcidin mimetic or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. 【0047】 In some embodiments, the present disclosure is a method of treating SCD in a subject, comprising administering to the subject a compound of formula (I): R1-X-Y-R2 (I) [In the formula, R1 is hydrogen, C1-C6 alkyl, C6-C12 aryl, C1-C20 alkanoyl, or pGlu; R2 is NH2 or OH; X is the amino acid sequence of formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (II) (In the formula, X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp, or absent; X2 is Thr, Ala, or D-Thr; X3 is His, Lys, D-His, or Lys; X4 is Phe, Ala, Dpa, or D-Phe; X5 is Pro, Gly, Arg, Lys, Ala, D-Pro, or bhPro; X6 is Ile, Cys, Arg, Lys, D-Ile, or D-Cys; X7 is Cys, Ile, Leu, Val, Phe, D-Ile, or D-Cys; X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu, or D-Ile; X9 is Phe or bhPhe; X10 is Lys, Phe, or absent) is; When Y is absent, X7 is Ile; Y is the amino acid sequence of formula III: Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (III) (In the formula, Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser, or absent; Y2 is Pro, Ala, Cys, Gly, or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp, or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr, or absent; Y5 is Lys, Met, Arg, Ala, or absent; Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val, or absent; Y7 is Trp, Lys, Gly, Ala, Ile, Val, or absent; Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg, or absent; Y9 is Cys, Tyr, or absent; Y10 is Met, Lys, Arg, Tyr, or absent; Y11 is Arg, Met, Cys, Lys, or absent; Y12 is Arg, Lys, Ala, or absent; Y13 is Arg, Cys, Lys, Val, or absent; Y14 is Arg, Lys, Pro, Cys, Thr, or absent; Y15 is Thr, Arg, or absent) 〕 administering a hepcidin mimetic peptide comprising or consisting of the same, or a pharmaceutically acceptable salt or solvate thereof; the peptide comprising Formula I is optionally pegylated at R1, X or Y; the side chains of the amino acids of the peptide are optionally conjugated to a lipophilic substituent or a polymeric moiety; Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid, and bhPro is β-homoproline, providing the method. In certain embodiments, SCD is sickle cell anemia (SS), sickle cell hemoglobin C disease (SC), sickle cell beta plus thalassemia, or sickle cell beta zero thalassemia. 【0048】 In certain embodiments of the methods described herein, the peptide of formula (I) comprises or consists of a disulfide bond formed between two Cys amino acid residues present in the peptide; for example, the thiol groups on the side chains of two cysteine residues in the peptide form a disulfide bond. In one embodiment, the peptide has a disulfide bond formed between two Cys amino acid residues present in the peptide. 【0049】 In certain embodiments of the methods described herein, R1 is hydrogen, isovaleric acid, isobutyric acid, or acetyl. 【0050】 In certain embodiments of the compounds of formula (I), X is an amino acid sequence of formula IV: X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (IV) wherein, X1 is Asp, Ida, pGlu, bhAsp, or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X6 is Ile, Cys, or Arg; X7 is Cys, Ile, Leu, or Val; X8 is Ile, Lys, Glu, Phe, Gln, or Arg; X10 is Lys or absent and is a peptide comprising or consisting of the same. In certain embodiments, X is a peptide having the amino acid sequence of formula IV. 【0051】 In some embodiments of the compounds of formula (I), X is an amino acid sequence of formula V: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (V) wherein, X1 is Asp, Ida, pGlu, bhAsp, or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Ile, Lys, Glu, Phe, Gln, or Arg; X10 is Lys or absent) A peptide comprising or consisting of. In certain embodiments, X is a peptide having the amino acid sequence of Formula V. 【0052】 In some embodiments of the methods described herein, the hepcidin mimetic has the amino acid sequence of Formula VI: R 1 -X-Y-R 2 (VI) Wherein, R 1 is hydrogen, isovaleric acid, isobutyric acid, or acetyl; R 2 is NH2 or OH; X has the amino acid sequence of Formula VII: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (VII) (wherein, X1 is Asp, Ida, pGlu, bhAsp, or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Ile, Lys, Glu, Phe, Gln, or Arg; X10 is Lys or absent) and; Y has the amino acid sequence of Formula VIII: Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (VIII) (wherein, Y1 is Gly, Glu, Val, or Lys; Y3 is Arg or Lys; Y5 is Arg or Lys; Y6 is Gly, Ser, Lys, Ile, or Arg; Y7 is Trp or absent; Y8 is Val, Thr, Asp, Glu or absent; Y10 is Lys or absent) is) a peptide comprising or consisting of the peptide or a pharmaceutically acceptable salt thereof, the peptide comprising or consisting of a disulfide bond between two Cys; the peptide optionally being pegylated at R 1 , X or Y; the side chains of the amino acids of the peptide optionally being conjugated to a lipophilic substituent or a polymeric moiety; Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid and bhPro is β-homoproline. In certain embodiments, the peptide has formula VI and the two Cys residues in the peptide form a disulfide bond. In other embodiments, the peptide has formula (VI) and the peptide is not cyclized. 【0053】 In certain embodiments of the methods described herein, the hepcidin mimetic has the following amino acid sequences: DTHFPICIFGPRSKGWVC (SEQ ID NO: 47); DTHFPCIIFGPRSKGWVCK (SEQ ID NO: 48); DTHFPCIIFEPRSKGWVCK (SEQ ID NO: 49); DTHFPCIIFGPRSKGWACK (SEQ ID NO: 50); DTHFPCIIFGPRSKGWVCKK (SEQ ID NO: 51); DTHFPCIIFVCHRPKGCYRRVCR (SEQ ID NO: 52); DTHFPCIKFGPRSKGWVCK (SEQ ID NO: 53); DTHFPCIKFKPRSKGWVCK (SEQ ID NO: 54); DTHFPCIIFGPRSRGWVCK (SEQ ID NO: 55); DTHFPCIKFGPKSKGWVCK (SEQ ID NO: 56); DTHFPCIKFEPRSKGCK (SEQ ID NO: 57); DTHFPCIKFEPKSKGWECK (SEQ ID NO: 58); DTHFPCIKFEPRSKKCK (SEQ ID NO: 59); DTHFPCIKFEPRSKGCKK (SEQ ID NO: 60); DTHFPCIKFKPRSKGCK (SEQ ID NO: 61); DTHFPCIKFEPKSKGCK (SEQ ID NO: 62); DTHFPCIKF (SEQ ID NO: 63); DTHFPCIIF (SEQ ID NO: 64); or DTKFPCIIF (SEQ ID NO: 65) a peptide comprising or consisting of one of the following: wherein the peptide is optionally pegylated at R1, X or Y; wherein the side chains of the amino acids of the peptide are optionally conjugated to a lipophilic substituent or a polymeric moiety, wherein the peptide optionally contains a disulfide bond between two Cys amino acid residues of the peptide. In certain embodiments, the peptide is cyclized via a disulfide bond formed between two Cys amino acid residues of the same peptide. In other embodiments, the peptide is linear, i.e., not cyclized via a disulfide bond. 【0054】 In certain embodiments of the methods described herein, the peptide has the following sequences: Isovaleric acid - DTHFPICIFGPRSKGWVC - NH2 (SEQ ID NO: 1); Isovaleric acid - DTHFPCIIFGPRSKGWVCK - NH2 (SEQ ID NO: 2); Isovaleric acid - DTHFPCIIFEPRSKGWVCK - NH2 (SEQ ID NO: 3); Isovaleric acid - DTHFPCIIFGPRSKGWACK - NH2 (SEQ ID NO: 4); Isovaleric acid - DTHFPCIIFGPRSKGWVCKK - NH2 (SEQ ID NO: 5); Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH2 (SEQ ID NO: 6); Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2 (SEQ ID NO: 7); Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2 (SEQ ID NO: 8); Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVC-NH2 (SEQ ID NO: 9); Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVC-NH2 (SEQ ID NO: 10); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH2 (SEQ ID NO: 11); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH2 (SEQ ID NO: 12); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2 (SEQ ID NO: 13); Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2 (SEQ ID NO: 14); Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2 (SEQ ID NO: 15); Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2 (SEQ ID NO: 16); Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2 (SEQ ID NO: 17); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))NH2 (SEQ ID NO: 18); Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH2 (SEQ ID NO: 19); Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH2 (SEQ ID NO: 20); Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH2 (SEQ ID NO: 21); Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH2 (SEQ ID NO: 22); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH2 (SEQ ID NO: 23); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2 (SEQ ID NO: 24); Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH2 (SEQ ID NO: 25); Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-NH2 (SEQ ID NO: 26); Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH2 (SEQ ID NO: 27); Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-NH2 (SEQ ID NO: 28); Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH2 (SEQ ID NO: 29); Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-NH2 (SEQ ID NO: 30); Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-NH2 (SEQ ID NO: 31); Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2 (SEQ ID NO: 32); Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2 (SEQ ID NO: 33); Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2 (SEQ ID NO: 34); Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2 (SEQ ID NO: 35); Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2 (SEQ ID NO: 36); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-NH2 (SEQ ID NO: 37); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2 (SEQ ID NO: 38); Isovaleric acid-DTHFPCIKF(K(PEG11-Palm))PRSK[Sar]CK-NH2 (SEQ ID NO: 39); Isovaleric acid-ETHFPCI(K(IsoGlu_Palm))FEPRSKGCK-NH2 (SEQ ID NO: 46); Isovaleric acid-DTHFPCIKF-NH2 (SEQ ID NO: 40); Hy-DTHFPCIKF-NH2 (SEQ ID NO: 41); Isovaleric acid-DTHFPCIIF-NH2 (SEQ ID NO: 42); Hy-DTHFPCIIKF-NH2 (SEQ ID NO: 43); Isovaleric acid-DTKFPCIIF-NH2 (SEQ ID NO: 44); or Hy-DTKFPCIIF-NH2 (SEQ ID NO: 45) comprises or consists of one of the following, and optionally, the peptide comprises or consists of a disulfide bond between two Cys amino acid residues of the peptide. In certain embodiments, the peptide has a disulfide bond formed between two Cys amino acid residues of the peptide. In certain embodiments, the peptide is cyclized via a disulfide bond formed between two Cys amino acid residues of the same peptide. In other embodiments, the peptide is linear, i.e., not cyclized via a disulfide bond. 【0055】 In certain embodiments of the methods described herein, the peptide is (a) 【Chem.】 (b) 【Chem.】 (c) 【Chem.】 (d) 【Chem.】 (e) 【Chem.】 (f) 【Chem.】 having a structure selected from, the amino acids being L-amino acids, and in each of Compounds 20, 25, 26, 27, 28 and 46, the thiol groups on the side chains of the two cysteine residues are joined together to form a disulfide bond. 【0056】 In another embodiment, the peptide is Compound 2, or a pharmaceutically acceptable salt thereof. 【0057】 In another embodiment, the peptide is Compound 3, or a pharmaceutically acceptable salt thereof. 【0058】 In another embodiment, the peptide is Compound 7, or a pharmaceutically acceptable salt thereof. 【0059】 In another embodiment, the peptide is Compound 8, or a pharmaceutically acceptable salt thereof. 【0060】 In another embodiment, the peptide is Compound 11, or a pharmaceutically acceptable salt thereof. 【0061】 In another embodiment, the peptide is Compound 14, or a pharmaceutically acceptable salt thereof. 【0062】 In another embodiment, the peptide is Compound 15, or a pharmaceutically acceptable salt thereof. 【0063】 In another embodiment, the peptide is Compound 16, or a pharmaceutically acceptable salt thereof. 【0064】 In another embodiment, the peptide is compound 18, or a pharmaceutically acceptable salt thereof. 【0065】 In another embodiment, the peptide is compound 19, or a pharmaceutically acceptable salt thereof. 【0066】 In another embodiment, the peptide is compound 20, or a pharmaceutically acceptable salt thereof. 【0067】 In another embodiment, the peptide is compound 21, or a pharmaceutically acceptable salt thereof. 【0068】 In another embodiment, the peptide is compound 22, or a pharmaceutically acceptable salt thereof. 【0069】 In another embodiment, the peptide is compound 23, or a pharmaceutically acceptable salt thereof. 【0070】 In another embodiment, the peptide is compound 24, or a pharmaceutically acceptable salt thereof. 【0071】 In another embodiment, the peptide is compound 26, or a pharmaceutically acceptable salt thereof. 【0072】 In another embodiment, the peptide is compound 27, or a pharmaceutically acceptable salt thereof. 【0073】 In another embodiment, the peptide is compound 28, or a pharmaceutically acceptable salt thereof. 【0074】 In another embodiment, the peptide is compound 32, or a pharmaceutically acceptable salt thereof. 【0075】 In another embodiment, the peptide is compound 34, or a pharmaceutically acceptable salt thereof. 【0076】 In some embodiments of the methods disclosed herein, the peptide is Compound 25, or a pharmaceutically acceptable salt thereof. 【0077】 In other embodiments of the methods disclosed herein, the peptide is Compound 46, or a pharmaceutically acceptable salt thereof. 【0078】 In some embodiments of the methods disclosed herein, the effective amount is from about 0.5 mg to about 100 mg, or from about 0.5 mg to about 50 mg, or from about 0.5 mg to about 35 mg, or from about 1 mg to about 24 mg, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg of a hepcidin compound disclosed herein or a pharmaceutically acceptable salt thereof. 【0079】 In some embodiments, the hepcidin mimetic disclosed herein is administered to a subject about twice a week, about once a week, about once every other week, or about once a month. In certain embodiments, the subject is administered the hepcidin mimetic or a pharmaceutically acceptable salt thereof about once a week. In certain embodiments, the hepcidin mimetic or a pharmaceutically acceptable salt thereof is administered to the subject about once every two weeks or about once a month. In some embodiments, the hepcidin mimetic or a pharmaceutically acceptable salt thereof is administered to the subject multiple times over a period of time, such as for at least six months, at least or about one year, at least or about two years, at least or about five years, or over the lifetime of the subject. 【0080】 In some embodiments of the methods disclosed herein, the hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a peptide, is administered in a composition (e.g., a pharmaceutical composition), and in some embodiments, the hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a peptide (or composition) is administered by subcutaneous injection. In some embodiments, the hepcidin mimetic or a pharmaceutically acceptable salt thereof, or a peptide (or composition) is administered about once a week over a period of time, such as for as long as necessary. In some embodiments, the hepcidin mimetic or a peptide (or composition) is administered about once every three days, about twice a week, about once every four days, about once every five days, about once a week, about once every two weeks, about once a month, about once every six weeks, about once every eight weeks, about once every two months, or about once every three months. In some embodiments, it is administered about once a week or about once every two weeks. In certain embodiments, it is administered about once a week. In some embodiments, it is administered about once every two weeks, about once a month, or about once every two months. 【0081】 In some embodiments of the methods disclosed herein, treatment of SCD results in a significant decrease in HCT in a subject in a dose-dependent manner. In some embodiments, the hematocrit level of the subject is 45% or less. In certain embodiments, the hematocrit of the subject is maintained in the range of about 37.5% to about 45% (or within the range acceptable for the subject's gender and pregnancy status) for a period of time, such as at least 1 month, at least 2 months, at least 6 months, or longer. In certain embodiments, the method or treatment regimen results in a decrease in hematocrit (HCT%) of at least 3%, at least 5%, at least 10% for at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer. 【0082】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in mean corpuscular volume (MCV) in the subject. In certain embodiments, the method of treating SCD results in a decrease in MCV of at least about 1 fL, about 3 fL, about 5 fL, about 10 fL, about 20 fL, about 25 fL, or about 30 fL. In some embodiments, the MCV decreases by at least 10%, at least 20%, at least 30%, at least 50%, at least 90%, or at least 95% during the treatment regimen, or for at least 1 month, at least 2 months, at least 6 months, or longer. 【0083】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the mean corpuscular hemoglobin (MCH) in a subject. In certain embodiments, a method of treating SCD results in a decrease in MCH of at least about 1, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 6 pg, about 7 pg, about 8 pg, about 9 pg or about 10 pg. In some embodiments, MCH increases by at least 10%, at least 20%, at least 30%, at least 50%, at least 100%, or at least 200% during the treatment regimen, or for at least 1 month, at least 2 months, at least 6 months or longer. 【0084】 In some embodiments of the methods disclosed herein, treatment of SCD results in an increase in the mean corpuscular hemoglobin concentration (MCHC) in a subject. In certain embodiments, a method of treating SCD results in an increase in MCHC of at least about 1 g / d, about 2 g / d, about 3 g / d, about 4 g / d, about 5 g / d, about 6 g / d, about 7 g / d, about 8 g / d, about 9 g / d, about 10 g / d, about 11 g / d, about 12 g / d, about 13 g / d, about 14 g / d or about 15 g / d during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0085】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the white blood cell (WBC) count in a subject. In certain embodiments, a method of treating SCD results in a decrease in WBC of at least about 1K cells / μL, about 2K cells / μL, about 3K cells / μL, about 4K cells / μL, about 5K cells / μL, about 6K cells / μL, about 7K cells / μL, about 8K cells / μL, about 9K cells / μL, about 10K cells / μL, about 15K cells / μL, about 20K cells / μL, about 25K cells / μL, about 30K cells / μL, or about 35K cells / μL. In certain embodiments, the decrease in WCB occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0086】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the number of lymphocytes in the subject. In certain embodiments, the method of treating SCD results in a decrease in the number of lymphocytes of at least about 1000 cells / μL, about 2000 cells / μL, about 3000 cells / μL, about 5000 cells / μL, about 10000 cells, about 12000 cells / μL, about 15000 cells / μL, about 20000 cells / μL, about 25000 cells / μL, about 28000 cells / μL or about 30000 cells / μL. In some embodiments, the number of lymphocytes decreases by at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 90% or at least 95% during the treatment regimen. In certain embodiments, the decrease in the number of lymphocytes occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0087】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the number of monocytes in the subject. In certain embodiments, the method of treating SCD results in a decrease in the number of monocytes of at least about 100 cells / μL, about 200 cells / μL, about 300 cells / μL, about 400 cells / μL, about 500 cells / μL, about 1000 cells / μL, about 1200 cells / μL, about 1500 cells / μL, about 2000 cells / μL, about 2500 cells / μL, about 2800 cells / μL or about 3000 cells / μL. In some embodiments, the number of monocytes decreases by at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 90% or at least 95% during the treatment regimen. In certain embodiments, the decrease in the number of monocytes occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0088】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the neutrophil count in the subject. In certain embodiments, a method of treating SCD results in a decrease in the neutrophil count of at least about 200 cells / μL, about 300 cells / μL, about 400 cells / μL, about 500 cells / μL, about 1000 cells / μL, about 2000 cells / μL, about 2500 cells / μL, about 2800 cells / μL, about 3000 cells / μL, about 4000 cells / μL, about 5000 cells / μL, about 6000 cells / μL, about 7000 cells / μL, about 7500 cells / μL, about 8000 cells / μL, about 8500 cells / μL, about 9000 cells / μL or 10000 cells / μL. In some embodiments, the neutrophil count decreases by at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 80%, at least 90% or at least 95% during the treatment regimen. In certain embodiments, the decrease in the neutrophil count occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0089】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in serum lactate dehydrogenase (LDH) in the subject. In certain embodiments, a method of treating SCD results in a decrease in LDH of at least about 100, about 200 / μL, about 300 / μL, about 400 / μL, about 500 / μL, about 600 / μL, about 700 / μL, about 800 / μL, about 900 / μL or about 1000 / μL. In some embodiments, LDH decreases by at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 80%, at least 90% or at least 95% during the treatment regimen. In certain embodiments, the decrease in LDH occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months or longer. 【0090】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the total bilirubin concentration in the subject. In certain embodiments, the method of treating SCD results in a decrease in the total bilirubin concentration of at least about 0.5 mg / μL, about 1.0 mg / μL, about 1.3 mg / μL, about 1.5 mg / μL, about 2 mg / μL, about 2.5 mg / μL, about 3 mg / μL, about 3.5 mg / μL, or about 4 mg / μL. In some embodiments, the total bilirubin concentration decreases by at least about 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 80%, at least 90%, or at least 95% during the treatment regimen. In certain embodiments, the decrease in bilirubin concentration occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer. 【0091】 In some embodiments of the methods disclosed herein, treatment of SCD results in a decrease in the reticulocyte count in the subject. In certain embodiments, the method of treating SCD results in a decrease in the absolute reticulocyte count of at least about 500 (K cells / uL), about 600 (K cells / uL), about 700 (K cells / uL), about 800 (K cells / uL), about 900 (K cells / uL), about 1000 (K cells / uL), about 1500 (K cells / uL), about 2000 (K cells / uL), or about 2500 (K cells / uL). In some embodiments, the reticulocytes decrease by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% during the treatment regimen. In certain embodiments, the decrease in reticulocytes occurs during a treatment regimen that lasts for at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer. 【0092】 In some embodiments, treatment of SCD with the peptides disclosed herein reduces MCHC, hemichrome aggregates, and extends the lifespan of red blood cells. 【0093】 In some embodiments, the treatment regimen comprises administration of a hepcidin mimetic about once a week, or about once every two weeks, two or more times, three or more times, four or more times, or several times, e.g., over a period, at least one month, at least two months, at least six months, or longer. 【0094】 In some embodiments, the sickle cell disease described herein can be treated by administering any of the hepcidin mimetics disclosed in any of US9,822,157, US10,030,061 and US9315545; PCT application publications WO15200916, WO17117411, WO18048944, WO18128828, WO17068089, WO2017117411, WO2019157268, WO2022026629, WO2022026631 and WO2022026633, the entire contents of each of which are incorporated herein by reference for all purposes. 【0095】 Administration and Pharmaceutical Compositions The peptides of formula I, II, III, IV, V, VI, VII or VIII, or the compounds disclosed herein or recited in the claims, or compound 25 or compound 46, or a pharmaceutically acceptable salt thereof, can be administered in pure form or in a state contained in a suitable pharmaceutical composition, by any of the acceptable modes of administration or agents providing similar utility. Thus, the administration can be, for example, in the form of solids, semi-solids, lyophilized powders, or liquid dosage forms, such as tablets, suppositories, pills, soft and hard gelatin dosages (which can be capsules or tablets), powders, solutions, suspensions or aerosols, specifically in unit dosage forms suitable for convenient administration in exact dosages, e.g., oral, nasal, parenteral (intravenous, intramuscular or subcutaneous), topical, transdermal, intravaginal, intravesical, intracerebroventricular or rectal administration. In one embodiment, the peptide is administered subcutaneously. 【0096】 The composition comprises a conventional pharmaceutical carrier or excipient and, as its active agent / one active agent, a compound of formula I, II, III, IV, V, VI, VII or VIII, or a compound disclosed herein or recited in the claims, or compound 25 or compound 46, or a pharmaceutically acceptable salt thereof, and may further contain a carrier, excipient, vehicle and / or adjuvant. 【0097】 Adjuvants include preservatives, wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances, emulsifying agents, and dispersing agents. The prevention of microbial activity can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. The use of agents that delay absorption, such as aluminum monostearate and gelatin, can result in sustained absorption of the injectable pharmaceutical form. 【0098】 Optionally, the pharmaceutical composition of the hepcidin mimetic or peptide disclosed herein may also contain small amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, antioxidants, etc., such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc. 【0099】 In some embodiments, the hepcidin mimetic, or pharmaceutical composition comprising a hepcidin mimetic, disclosed herein is in unit dosage form. In such form, the composition is divided into unit doses containing one or more active ingredients in suitable amounts. The unit dosage form can be provided as a packaged preparation that houses an individual amount of the preparation within a packaging material, e.g., a packaged tablet, capsule, or powder in a vial or ampoule. The unit dosage form can also be, e.g., a capsule, cachet or tablet itself, or it can be a suitable number of any of these packaged forms. The unit dosage form can also be provided in a single-dose injectable form, e.g., in the form of a pen-type device containing a liquid phase (typically an aqueous phase) composition. The composition can be formulated for any suitable route and means of administration, e.g., for any one of the routes and means of administration disclosed herein. 【0100】 In certain embodiments, the hepcidin mimetic, or pharmaceutical composition comprising a hepcidin mimetic, is suspended in a sustained-release matrix. The sustained-release matrix, as used herein, is a matrix made of a material that is capable of degradation by enzymatic hydrolysis or acid-base hydrolysis or by dissolution, typically a polymer. The matrix is subjected to the action of enzymes and body fluids when inserted into the body. The sustained-release matrix is preferably selected from biocompatible materials such as liposomes, polylactide (polylactic acid), polyglycolide (a polymer of glycolic acid), polylactide co-glycolide (a copolymer of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicones. One embodiment of the biodegradable matrix is a matrix of either polylactide or polyglycolide or of polylactide co-glycolide (a copolymer of lactic acid and glycolic acid). 【0101】 In certain embodiments, the composition is administered parenterally, subcutaneously, or orally. In some embodiments, the composition is administered orally, intracerebroventricularly, intravaginally, intraperitoneally, rectally, topically (e.g., by powder, ointment, drops, suppository, or transdermal patch including delivery into the vitreous body, intranasally, and by inhalation), or buccally. As used herein, the term "parenteral" refers to a mode of administration that includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions. Thus, in certain embodiments, the composition is formulated for delivery by any of these routes of administration. 【0102】 In certain embodiments, a pharmaceutical composition for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension, or emulsion, or a sterile powder for reconstitution into a sterile injectable solution or dispersion immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, beta-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Sustained absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin. 【0103】 As injectable depot forms, there are those made by forming a microcapsule matrix of hepcidin mimics with one or more biodegradable polymers, such as polylactide - polyglycolide, poly(ortho esters), poly(anhydrides), and (poly)glycols such as PEG. The release rate of the hepcidin mimics can be controlled according to the ratio of the peptide to the polymer and the nature of the specific polymer used. Injectable depot formulations are also prepared by encapsulating the hepcidin mimics in liposomes or microemulsions that are compatible with living tissues. 【0104】 The injectable formulation can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media immediately before use. 【0105】 The hepcidin mimics and peptides disclosed herein may also be administered with 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 single - layer or multi - layer hydrated liquid crystals dispersed in an aqueous medium. Any non - toxic and physiologically acceptable metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain stabilizers, preservatives, excipients, etc. in addition to the hepcidin mimics disclosed herein. In certain embodiments, the lipids include phospholipids, including both natural and synthetic phosphatidylcholines (lecithins) and serines. Methods of forming liposomes are known in the art. 【0106】 The pharmaceutical compositions used in the present invention suitable for parenteral administration may generally include sterile aqueous solutions and / or suspensions of peptide inhibitors that are isotonic with the recipient's blood using, for example, sodium chloride, glycerin, glucose, mannitol, sorbitol, etc. 【0107】 In some embodiments, the pharmaceutical compositions and hepcidin mimetics disclosed herein can be prepared for oral administration according to any of the methods, techniques, and / or delivery vehicles described herein. Further, one of ordinary skill in the art will fully understand that the hepcidin mimetic can be reformulated or incorporated into a system or delivery vehicle not disclosed herein but well-known in the art and suitable for use in oral delivery of peptides. 【0108】 In certain embodiments, formulations for oral administration include adjuvants (e.g., resorcinol and / or non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) for artificially increasing the permeability of the intestinal wall, and / or enzyme inhibitors (e.g., pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFF), or trasylol) for inhibiting enzymatic degradation. In certain embodiments, solid dosage forms of hepcidin mimetic for oral administration can 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, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms can 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, flavoring agents, or fragrances. 【0109】 In some embodiments, an oral dosage form or unit dose suitable for use with the hepcidin mimetic disclosed herein may include a mixture of the hepcidin mimetic and a non-drug component or excipient, and other non-reusable materials that may be considered either raw materials or packaging materials. The oral composition may include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, an oral dosage form is provided that includes an effective amount of a hepcidin mimetic, the dosage form including at least one of pills, tablets, capsules, gels, pastes, drinks, syrups, ointments, and suppositories. In some cases, an oral dosage form is provided that is designed and configured to provide delayed release of the hepcidin mimetic in the small intestine and / or colon of a subject. 【0110】 In one embodiment, an oral pharmaceutical composition comprising a hepcidin mimetic and comprising an enteric coating designed to delay release of the hepcidin mimetic in the small intestine. In at least some embodiments, a pharmaceutical composition is provided as a delayed release pharmaceutical formulation comprising the hepcidin mimetic disclosed herein and a protease inhibitor such as aprotinin. In some cases, the pharmaceutical composition of the present invention comprises an enteric coating that is soluble in gastric juice having a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition is provided that comprises an enteric coating comprising a polymer having dissociable carboxyl groups, such as derivatives of cellulose, such as hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and similar cellulose derivatives, as well as other carbohydrate polymers. 【0111】 In one embodiment, a pharmaceutical composition comprising a hepcidin mimetic disclosed herein is provided with an enteric coating, which is designed to protect and release the pharmaceutical composition in a controlled manner within the lower gastrointestinal tract of a subject and to avoid systemic side effects. The hepcidin mimetics disclosed herein can be encapsulated, coated, engaged or associated within any suitable oral drug delivery system or component in addition to an enteric coating. For example, in some embodiments, the hepcidin mimetics disclosed herein are provided with a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, micelles and other lipid-based systems. 【0112】 To overcome peptide degradation in the small intestine, some embodiments of the invention include a hydrogel polymer carrier system containing a hepcidin mimetic disclosed herein, whereby the hydrogel polymer protects the hepcidin mimetic from proteolysis in the small intestine and / or colon. The hepcidin mimetics disclosed herein can be further formulated for use in carrier systems designed to increase the dissolution kinetics of the peptide and enhance intestinal absorption. These methods include the use of liposomes, micelles and nanoparticles to enhance gastrointestinal permeability of the peptide. 【0113】 One or more hepcidin mimetics disclosed herein can also be combined with various bioreactive systems to provide pharmaceutical agents for oral delivery. In some embodiments, the hepcidin mimetics disclosed herein are combined with a bioreactive system, such as a hydrogel, and a mucoadhesive polymer having a hydrogen bonding group (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan, and alginate) to provide a therapeutic agent for oral administration. Other embodiments are methods of optimizing or extending the drug residence time of the hepcidin mimetics disclosed herein, the method comprising modifying the surface of the hepcidin mimetic to include mucoadhesive properties by hydrogen bonding, a polymer having linked mucin, and / or hydrophobic interactions. These modified peptide molecules may exhibit an increase in drug residence time within a subject that is consistent with the desired characteristics of the present invention. Additionally, a targeted mucoadhesive system may specifically bind to receptors on the surface of enterocytes and M cells, thereby further enhancing the uptake of particles containing the hepcidin mimetic. 【0114】 Another embodiment is a method for the oral delivery of the hepcidin mimetic disclosed herein, the method comprising providing the hepcidin mimetic to a subject in combination with a permeation enhancer that promotes the transport of the peptide across the intestinal mucosa by enhancing paracellular or transcellular permeation. For example, in one embodiment, a permeation enhancer is combined with the hepcidin mimetic, the permeation enhancer comprising at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In one embodiment, a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino]caprylate is used to form a weak non-covalent association with the hepcidin mimetic of the invention, which advantageously acts on membrane transport and thus dissociation upon reaching the bloodstream. In another embodiment, the hepcidin mimetic disclosed herein is conjugated to oligoarginine, thereby enhancing the cellular permeation of the peptide into various cell types. Further, in one embodiment, a non-covalent bond is formed between the peptide disclosed herein and a permeation enhancer selected from the group consisting of cyclodextrin (CD) and a dendrimer, the permeation enhancer reducing peptide aggregation and improving the stability and solubility of the hepcidin mimetic molecule. 【0115】 In other embodiments, methods of treating a subject with a hepcidin mimetic disclosed herein having an extended half-life are provided herein. In one embodiment, the present disclosure provides a hepcidin mimetic having a half-life in vitro or in vivo (e.g., when administered to a human subject) of at least several hours to one day sufficient to administer a therapeutically effective amount once daily (q.d.) or twice daily (b.i.d.). In another embodiment, the hepcidin mimetic has a half-life of at least three days sufficient to administer a therapeutically effective amount once weekly (q.w.). Further, in another embodiment, the hepcidin mimetic has a half-life of at least eight days sufficient to administer a therapeutically effective amount once every two weeks (b.i.w.) or once monthly. In another embodiment, the hepcidin mimetic is derivatized or modified such that it has a longer half-life compared to an underivatized or unmodified hepcidin mimetic. In another embodiment, the hepcidin mimetic contains one or more chemical modifications to extend its serum half-life. 【0116】 Dosage The hepcidin mimetic of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, will be administered in a therapeutically effective amount that will vary depending on various factors including the activity of the particular compound used, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combinations, the severity of the particular disease state, and the host being treated. The hepcidin mimetic disclosed herein can be administered to a subject at a dosage level in the range of about 0.1 to about 1,000 mg per day. For a healthy human adult having a body weight of about 70 kilograms, an example of a dosage is in the range of about 0.01 to about 100 mg per kilogram of body weight per day. However, the specific dosage used can vary. For example, the dosage can be determined by many factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound used. Determination of the optimal dosage for a particular patient is well known to those of ordinary skill in the art. 【0117】 The total daily dosage of the hepcidin mimics and compositions disclosed herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage levels for any particular subject will depend on a variety of factors including: a) the disorder being treated and the severity of the disorder; b) the activity of the specific compound being used; c) the specific composition being used, the age, weight, general health, gender and diet of the patient; d) the time of administration, route of administration and rate of excretion of the specific hepcidin mimic being used; e) the duration of the treatment; f) drugs used in combination with or coincidentally administered with the specific hepcidin mimic being used, as well as similar factors well known in the medical arts. 【0118】 In some embodiments, the total daily dosage of the hepcidin mimics disclosed herein, administered as a single dose or divided doses to a human or other mammalian host, can be, for example, in an amount of from 0.0001 to 300 mg / kg body weight per day, or from 1 to 300 mg / kg body weight per day. In certain embodiments, the dosage of the hepcidin mimics disclosed herein is administered in one or more doses, for example 1 to 3 doses, and is from about 0.0001 to about 100 mg / kg body weight per day, such as from about 0.0005 to about 50 mg / kg body weight per day, such as from about 0.001 to about 10 mg / kg body weight per day, such as from about 0.01 to about 1 mg / kg body weight per day, or from about 0.1 to about 10 mg / kg body weight per day, or from about 0.1 to about 35 mg / kg body weight per day, or from about 0.5 to about 25 mg / kg body weight per day. 【0119】 In some embodiments, the total dosage is, for example in the case of a human patient, from about 10 mg to about 100 mg, or from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg. In some embodiments, the hepcidin mimic is provided to the subject once a week. In some other embodiments, the hepcidin mimic is provided to the subject twice a week, for example in the case of a human patient. 【0120】 In more specific embodiments, the total dosage is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg or about 80 mg, once or twice a week for a human patient. In more specific embodiments, the total dosage is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg or about 80 mg, approximately every other week or once a month for a human patient. 【0121】 In various embodiments, the hepcidin mimetic disclosed herein can be administered continuously (e.g., by intravenous administration or another continuous drug administration method) or intermittently, typically at regular intervals, depending on the desired dosage and pharmaceutical composition selected by an expert skilled in the art for a particular subject. Examples of dosing intervals for regular administration include once a day, twice a day, once every two days, once every three days, once every four days, once every five days or once every six days, once a week or twice a week, once a month or twice a month, etc. 【0122】 Such a regular dosing regimen of the hepcidin mimetic of the present invention may be beneficial to be interrupted over a period of time so that, in certain circumstances, such as during chronic long-term administration, the subject receiving the medication reduces the level of the medication or discontinues receiving the medication, which is often referred to as the attainment of a "drug holiday". The drug holiday may, for example, be useful in maintaining or restoring sensitivity to the drug, particularly during chronic long-term treatment, or in reducing undesirable side effects due to chronic long-term treatment of the subject with the drug. The timing of the drug holiday is determined by the timing of the regular dosing regimen and the purpose of attaining the drug holiday (e.g., to restore drug sensitivity and / or to reduce undesirable side effects due to continuous long-term administration). In some embodiments, the drug holiday may be to reduce the dosage of the drug (e.g., below the therapeutically effective amount over a period of time). In other embodiments, the administration of the drug is discontinued over a period of time and then administration is resumed using the same or a different (e.g., lower or higher dosage and / or dosing frequency) dosing regimen. Thus, the drug holiday of the present invention may be selected from a wide range of periods and dosing regimens. Exemplary drug holidays are drug holidays of 2 or more days, 1 week or more, or 1 month or more, up to about 24 months. Thus, the regular once-daily dosing regimen with the peptide, peptidomimetic or dimer of the present invention may be interrupted, for example, by a drug holiday of 1 week, or 2 weeks, or 4 weeks, after which the previous regular dosing regimen (e.g., once-daily or once-weekly dosing regimen) is resumed. Various other drug holiday regimens are envisioned to be useful in administering the hepcidin mimetic of the present invention. 【0123】 Thus, the hepcidin mimetic can be delivered by an administration regime that includes two or more dosing periods separated by each drug holiday period. 【0124】 During each dosing period, the hepcidin mimetic is administered to the recipient subject in a therapeutically effective amount according to a predetermined dosing pattern. The dosing pattern can include continuous administration of the drug to the recipient subject over the duration of the dosing period. Alternatively, the dosing pattern can include administering to the recipient subject multiple doses of the hepcidin mimetic, separated by a dosing interval. 【0125】 The dosing pattern can include at least 2 doses per dosing period, at least 5 doses per dosing period, at least 10 doses per dosing period, at least 20 doses per dosing period, at least 30 doses per dosing period, or more doses per dosing period. 【0126】 The dosing interval can be a regular dosing interval as shown above, and can be, for example, once a day, twice a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days or once every 6 days, once a week or twice a week, once a month or twice a month, or a less frequent but regular dosing interval, depending on the specific dosing formulation, bioavailability and pharmacokinetic profile of the hepcidin mimetic disclosed herein. 【0127】 The dosing period can 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. 【0128】 If the dosing pattern includes multiple doses, the duration of the subsequent drug-free period is longer than the dosing interval used in that dosing pattern. If the dosing interval is irregular, the duration of the drug-free period can be made longer than the average interval between doses throughout the dosing period. Alternatively, the duration of the drug-free period can be made longer than the longest interval between consecutive doses during the dosing period. 【0129】 The duration of the drug-free period can be at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times the duration of the dosing interval (or its average) associated therewith. 【0130】 Within these constraints, the drug-free period can 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 dosing pattern during the previous dosing period. 【0131】 The dosing regime includes at least two dosing periods. Successive dosing periods are separated by respective drug-free periods. Thus, the dosing regime includes at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30, or more dosing periods, with each dosing period separated by its respective drug-free day. 【0132】 Successive dosing periods may utilize the same dosing pattern, but this is not necessarily desirable or required. However, when administering other drugs or active agents in combination with the hepcidin mimetic disclosed herein, usually the same combination of drugs or active agents is given during successive dosing periods. In certain embodiments, the subject is human. 【0133】 The hepcidin mimics of the present invention can be produced using methods known in the art, including chemical synthesis, biosynthesis using recombinant DNA methods or in vitro synthesis, and solid-phase synthesis, in addition to the methods described in the examples herein. For example, see Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J.K. Setlow ed., Plenum Press, NY, pp. 1-19, Merrifield (1964) J Amer Chem Soc 85:2149, Houghten (1985) PNAS USA 82:5131-5135, and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are hereby incorporated by reference. The hepcidin mimics of the present invention can be purified using protein purification techniques known in the art, such as reverse-phase high performance liquid chromatography (HPLC), ion exchange or immunoaffinity chromatography, filtration or size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl (1973) Biochem. 12(16):3121-3126, and Scopes (1982) Protein Purification, Springer-Verlag, NY, which are hereby incorporated by reference. Alternatively, the hepcidin mimics of the present invention can be made by recombinant DNA techniques known in the art. Accordingly, polynucleotides encoding the polypeptides of the present invention are contemplated herein. In certain preferred embodiments, the polynucleotide is isolated. As used herein, "isolated polynucleotide" refers to a polynucleotide in an environment different from that in which it naturally occurs. 【0134】 The actual methods for preparing such dosage forms will be known or apparent to those skilled in the art, see, for example, Remington’s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). In any event, the composition to be administered contains a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof for treating the condition in accordance with the teachings of the present disclosure. 【0135】 The peptides disclosed herein, including hepcidin mimetics, can be produced using methods known in the art, such as chemical synthesis, biosynthesis using recombinant DNA methods or in vitro synthesis, and solid-phase synthesis. See, for example, PCT Application Publication Nos. WO2014 / 145561 and WO2015 / 200916, Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J.K. Setlow ed., Plenum Press, NY, pp. 1-19, Merrifield (1964) J Amer Chem Soc 85:2149, Houghten (1985) PNAS USA 82:5131-5135, and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are hereby incorporated herein by reference. The peptides disclosed herein can be purified using protein purification techniques known in the art, such as reverse-phase high-performance liquid chromatography (HPLC), ion-exchange or immunoaffinity chromatography, filtration or size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl (1973) Biochem. 12(16):3121-3126, and Scopes (1982) Protein Purification, Springer-Verlag, NY, which are hereby incorporated herein by reference. Alternatively, the peptides can be made by recombinant DNA techniques known in the art. 【0136】In certain embodiments, the peptides disclosed herein can be PEGylated. As used herein, "polyethylene glycol" or "PEG" is a polyether compound of the general formula H-(O-CH2-CH2)n-OH. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE) depending on its molecular weight. PEG, PEO, or POE, as used herein, refers to an oligomer or polymer of ethylene oxide. Although these three names are chemically synonymous, PEG tends to refer to oligomers and polymers with a molecular weight of less than 20,000 Da, PEO refers to polymers with a molecular weight of more than 20,000 Da, and POE tends to refer to polymers of any molecular weight. PEG and PEO are liquids or low melting point solids depending on their molecular weight. Throughout the present disclosure, the three names are used interchangeably. PEG is prepared by the polymerization of ethylene oxide and is commercially available over a wide range of molecular weights from 300 Da to 10,000,000 Da. PEGs and PEOs of different molecular weights are used for different applications and have different physical properties (e.g., viscosity) due to the effect of chain length, but their chemical properties are substantially the same. PEG moieties include polyethylene glycol (PEG), homopolymers or copolymers of PEG, monomethyl-substituted polymers of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998), Bioconjugate Chem. 6:150 (1995), and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also included are PEGs prepared for the purpose of half-life extension, such as mono-activated alkoxy-terminated polyalkylene oxides (POA), such as monomethoxy-terminated polyethylene glycol (mPEG), and bis-activated polyethylene oxides (glycols) or other PEG derivatives are contemplated. Suitable PEGs vary widely in weight, for example, in the range of about 200 Da to about 40,000 Da, or about 200 Da to about 60,000 Da, and any of these can be used for the purposes of the present disclosure.In certain embodiments, PEG having a molecular weight of 200 Da to 2,000 Da, or 200 Da to 500 Da is used. Depending on the initiator used in the polymerization process, different forms of PEG may be used, and common initiators are monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated as mPEG. Lower molecular weight PEGs are also available as pure oligomers called monodisperse, uniform or discrete types. These are used in certain embodiments of the present disclosure. 【0137】 PEGs are also available in various shapes. Branched PEGs have 3 to 10 PEG chains originating from a central core group, star PEGs have 10 to 100 PEG chains originating from a central core group, and comb PEGs have multiple PEG chains grafted at right angles to the polymer backbone. PEGs may also be linear. The numbers often included in the name of PEG indicate its average molecular weight (for example, PEG with n = 9 will have an average molecular weight of approximately 400 daltons and will be named PEG400). 【0138】 As used herein, "pegylation" is the act of covalently coupling a PEG structure to the peptide inhibitor of the present invention, after which the peptide inhibitor is called a "PEGylated peptide inhibitor". In certain embodiments, the PEG of the pegylated side chain is PEG having a molecular weight of about 200 Da to about 40,000 Da. 【0139】 In various embodiments, the agent is present in a pharmaceutical composition comprising one or more pharmaceutically acceptable diluents, carriers or excipients. Pharmaceutically acceptable carriers, diluents or excipients refer to any type of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in "Remington’s Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate buffered saline, which are slightly acidic or at physiological pH, can be used. Suitable pH buffers can 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 acetate (e.g., as sodium acetate), or mixtures thereof. The term further encompasses any carrier agent listed in the United States Pharmacopeia for use in animals, including humans. 【Example】 【0140】 The following examples illustrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and conventional to those skilled in the art, unless otherwise specifically described in detail. 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 its entirety. Therefore, they should in no way be considered as limiting the scope of the present invention. Abbreviations: DCM: Dichloromethane DMF: N,N-Dimethylformamide NMP: N-Methylpyrrolidone HBTU: O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate HATU: 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate DCC: Dicyclohexylcarbodiimide NHS: N-Hydroxysuccinimide DIPEA: Diisopropylethylamine EtOH: Ethanol Et2O: Diethyl ether Hy: Hydrogen TFA: Trifluoroacetic acid TIS: Triisopropylsilane ACN: Acetonitrile HPLC: High Performance Liquid Chromatography ESI-MS: Electrospray Ionization Mass Spectrometry PBS: Phosphate Buffered Saline Boc: t-Butyloxycarbonyl Fmoc: Fluorenylmethyloxycarbonyl Acm: Acetamidomethyl IVA: Isovaleric acid (or isovaleryl) 【0141】 K( ): In the peptide sequences provided herein, when a compound or chemical group is presented within parentheses immediately following a lysine residue, the compound or chemical group within the parentheses should be understood to be a side chain conjugated to the lysine residue. Thus, for example, but not by way of limitation, K-[(PEG8)]- represents that the PEG8 moiety is conjugated to the side chain of lysine. 【0142】 Palm: Represents the conjugation of palmitic acid (palmitoyl). 【0143】 As used herein, "C( )" refers to a cysteine residue involved in a particular disulfide bridge. For example, hepcidin has four disulfide bridges: the first is between two C(1) residues, the second is between two C(2) residues, the third is between two C(3) residues, and the fourth is between two C(4) residues. Thus, in some embodiments, the sequence of hepcidin is as follows: Hy-DTHFPIC(1)IFC(2)C(3)GC(2)C(4)HRSKC(3)GMC(4)C(1)KT-OH (SEQ ID NO: 66) and the sequences of other peptides can optionally be described in a similar manner. 【0144】 Example 1 Synthesis of Peptidomimetics Unless otherwise specified, the reagents and solvents used below were commercially available as standard laboratory reagents or analytical grade and were used without further purification. 【0145】 Procedure for Solid-Phase Synthesis of Peptides The peptidomimetics of the present invention were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. Rink-amide resin was used for the C-terminal amide, although Wang resin and trityl resin were also used to generate the C-terminal acid. The side-chain protecting groups were as follows: Glu, Thr, and Tyr: O-t-butyl; Trp and Lys: t-Boc (t-butyloxycarbonyl); Arg: N-gamma-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; His, Gln, Asn, Cys: trityl. Acm (acetamidomethyl) was also used as a Cys protecting group for selective disulfide bridge formation. For coupling, a 4- to 10-fold excess solution containing Fmoc amino acid, HBTU, and DIPEA (1:1:1.1) in DMF was added to the swollen resin [HBTU: O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, DIPEA: diisopropylethylamine, DMF: dimethylformamide]. To improve the coupling efficiency in difficult regions, HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) was used instead of HBTU. Removal of the Fmoc protecting group was accomplished by treatment with a (2:1) solution of DMF and piperidine. 【0146】 Procedure for cleaving the peptide from the resin Side-chain deprotection and cleavage of the peptidomimetic (e.g., compound number 2) was accomplished by stirring the dry resin in a solution containing trifluoroacetic acid, water, ethanedithiol, and triisopropylsilane (90:5:2.5:2.5) for 2 to 4 hours. After removal of the TFA, the peptide was precipitated using ice-cold diethyl ether. The solution was centrifuged, the ether was removed by decantation, and then a second wash with diethyl ether was performed. The peptide was dissolved in a solution of acetonitrile and water (1:1) containing 0.1% TFA (trifluoroacetic acid), and the resulting solution was filtered. The quality of the linear peptide was evaluated using electrospray ionization mass spectrometry (ESI-MS). 【0147】 Procedure for the purification of the peptide The purification of the peptide of the present invention (e.g., Compound No. 2) was accomplished using reverse-phase high-performance liquid chromatography (RP-HPLC). The analysis was performed at a flow rate of 1 mL / min using a C18 column (3 μm, 50×2 mm). The purification of the linear peptide was accomplished using preparative RP-HPLC on a C18 column (5 μm, 250×21.2 mm) at a flow rate of 20 mL / min. The separation was accomplished using a linear gradient of Buffer B in Buffer A (Buffer A: aqueous solution of 0.05% TFA, Buffer B: water containing 0.043% TFA and 90% acetonitrile). 【0148】 Procedure for the oxidation of the peptide Method A (oxidation of a single disulfide). The oxidation of the unprotected peptide of the present invention was accomplished by dropwise addition of iodine (1 mg per 1 mL) contained in MeOH to the peptide-containing solution (ACN:H2O, 7:3, 0.5% TFA). After stirring for 2 minutes, ascorbic acid was added little by little until the solution became clear, and the sample was immediately loaded onto HPLC for purification. 【0149】 Method B (selective oxidation of two disulfides). When more than one disulfide was present, selective oxidation was often performed. The oxidation of the free cysteine was accomplished with the peptide at 1 mg / 10 mL in an NH4CO3 solution at pH 7.6. After stirring for 24 hours, prior to purification, the solution was acidified to pH 3 with TFA and then lyophilized. Subsequently, the obtained singly oxidized peptide (having ACM-protected cysteine) was subjected to oxidation / selective deprotection using an iodine solution. The peptide (1 mg per 2 mL) was dissolved in 80:20 MeOH / H2O, and the reaction solvent in which iodine was dissolved was added to the reactant at room temperature (final concentration: 5 mg / mL). The solution was stirred for 7 minutes, and then ascorbic acid was added little by little until the solution became clear. Thereafter, the solution was directly loaded onto HPLC. 【0150】 Method C (natural oxidation). When more than one disulfide was present and selective oxidation was not performed, natural oxidation was carried out. Natural oxidation was accomplished in the presence of oxidized and reduced glutathione using a 100 mM NH4CO3 (pH 7.4) solution (peptide:GSSG:GSH, 1:10, 100) (molar ratio of peptide / GSH / GSSG, 1:100:10). After stirring for 24 hours, prior to purification by RP-HPLC, the solution was acidified to pH 3 with TFA and then lyophilized. 【0151】 Procedure for cysteine oxidation to generate dimers. Oxidation of the unprotected peptide of the present invention was accomplished by dropwise addition of iodine (1 mg per 1 mL) contained in MeOH to the peptide-containing solution (ACN:H2O, 7:3, 0.5% TFA). After stirring for 2 minutes, ascorbic acid was added in small portions until the solution became clear, and the sample was immediately loaded onto HPLC for purification. 【0152】 Procedure for dimerization. One equivalent (abbreviated "eq") of an acid was treated with both N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC), both at 2.2 eq at a final concentration of 0.1 M in NMP (N-methylpyrrolidone) to preactivate glyoxylic acid (DIG), IDA, or Fmoc-β-Ala-IDA as N-N-hydroxysuccinimide esters. For PEG13 and PEG25 linkers, these chemical entities were purchased in a preformed state as active succinimide esters. Approximately 0.4 eq of the active ester was slowly added in small portions to the peptide (1 mg / mL) in NMP. The solution was left stirring for 10 minutes, and then an additional approximately 0.05 eq of the linker was added slowly in 2 - 3 equal portions. The solution was left stirring for an additional 3 hours, after which the solvent was removed under vacuum and the residue was purified by reverse-phase HPLC. A further step of stirring the peptide in 20% piperidine in DMF (2×10 minutes) was carried out, followed by further reverse-phase HPLC purification. 【0153】 One skilled in the art will fully understand that the compounds of the present invention can be produced using standard methods of peptide synthesis. 【0154】 Linker activation and dimerization Peptide monomer subunits were linked as described below to form hepcidin mimetic peptide dimers. 【0155】 Small-scale DIG linker activation procedure: 5 mL of NMP was added to a glass vial containing IDA diacid (304.2 mg, 1 mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 equivalents, 2.2 mmol), and a stir bar. The mixture was stirred at room temperature to completely dissolve the solid starting materials. Then, N,N'-dicyclohexylcarbodiimide (DCC, 453.9 mg, 2.2 equivalents, 2.2 mmol) was added to the mixture. A precipitate appeared within 10 minutes, and the reaction mixture was further stirred at room temperature overnight. Then, the reaction mixture was filtered to remove the precipitated dicyclohexylurea (DCU). The activated linker was kept in a sealed vial prior to use for dimerization. The nominal concentration of the activated linker was approximately 0.20 M. 【0156】 For dimerization using the PEG linker, no pre-activation step was required. A commercially available pre-activated bifunctional PEG linker was used. 【0157】 Dimerization Procedure: 2 mL of anhydrous DMF was added to a vial containing the peptide monomer (0.1 mmol). The pH of the peptide was adjusted to 8 - 9 with DIEA. Subsequently, the activated linker (IDA, or PEG13, PEG25) (0.48 equivalents relative to the monomer, 0.048 mmol) was added to the monomer solution. The reaction mixture was stirred at room temperature for 1 hour. The completion of the dimerization reaction was monitored using analytical HPLC. The time required for the completion of the dimerization reaction varied depending on the linker. After the reaction was completed, the peptide was precipitated in cold ether and centrifuged. The ether layer of the supernatant was discarded. The precipitation step was repeated twice. Subsequently, the crude dimer was purified using reverse-phase HPLC (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient of 15% B, changing to 45% B over 60 minutes, flow rate 15 ml / min). Then, the fractions containing the pure product were lyophilized using a freeze dryer. 【0158】 Conjugation of the half-life extension moiety Peptide conjugation was performed on resin. Lys(ivDde) was used as the key amino acid. After the assembly of the peptide on the resin, selective deprotection of the ivDde group occurred using 2% hydrazine in DMF for 5 minutes, repeated 3 times for 5 minutes each. Activation and acylation of the linker were carried out using 1 - 2 equivalents of HBTU and DIEA for 3 hours, Fmoc was removed, and subsequently, a second acylation with fatty acid was performed to obtain the conjugated peptide. 【0159】 Example 2 Efficacy Test of Hepcidin Mimetic in a Mouse Model of Sickle Cell Disease Experimental Method Compound 46, a hepcidin mimetic, was administered subcutaneously to Townes SCD mice at 1.0 mg / kg (Group 3, N = 9) or 2.5 mg / kg (Group 4, N = 9). Thirty-six Townes SCD and six 129S1 / SvlmJ (wild-type) female mice, 5 weeks old at the time of delivery. Wild-type mice in the control group (Group 1, N = 6), as well as another group of SCD mice (Group 2, N = 9) were treated with vehicle. Administration was performed three times a week (TIW) for all mice. Throughout the study, all mice were housed on an iron-adjusted diet (TD.140258, 35 ppm iron). Collection and necropsy were performed 24 hours after the final administration of the compound or vehicle. At week 4 of the study, animals from each group were euthanized, whole blood was collected with EDTA for CBC, and serum was collected for hemolysis biomarker analysis. Spleen and liver weights at the end were measured. Liver, spleen, kidney, heart, and brain were collected for future analysis. Serum and urine were collected to analyze chemical markers such as bilirubin, LDH (lactate dehydrogenase), haptoglobin, urinary creatinine, total urinary protein, and urinary urea nitrogen. 【0160】 Spleen weight and spleen-to-body weight ratio As shown in A and B of Figure 1, spleen size in SCD mice was significantly larger compared to healthy control mice. In SCD mice treated with the hepcidin mimetic disclosed herein, such as Compound 46, spleen weight and spleen-to-body weight ratio were significantly and dose-dependently lower compared to the vehicle case. 【0161】 Liver weight and liver-to-body weight ratio As shown in A and B of Figure 2, liver size in SCD mice was significantly enlarged compared to healthy control mice. Compared to vehicle-treated SCD mice, liver weight and liver-to-body weight ratio in SCD mice treated with the hepcidin mimetic disclosed herein, such as Compound 46, were significantly lower in a dose-dependent manner. 【0162】 Red blood cells and hemoglobin As shown in A and B of FIG. 3, the red blood cell (RBC) count and Hgb in SCD mice are significantly lower compared to healthy control mice. In the case of the hepcidin mimetic disclosed herein at a dose of 2.5 mg / kg, such as Compound 46, the RBC count significantly decreases. The Hgb level is significantly decreased in all three dose groups, especially in the high-dose group. 【0163】 Reticulocyte count As shown in A and B of FIG. 4, the reticulocyte count was performed not only by an automated analyzer but also manually by counting the number of positively stained cells found in 500 red blood cells and calculating the percentage from freshly methylene blue-stained blood smears. The percentage of reticulocytes in SCD mice was significantly higher compared to healthy controls. The hepcidin mimetic disclosed herein at a dose of 2.5 mg / kg, such as Compound 46, significantly decreased the percentage of reticulocytes compared to the vehicle control. 【0164】 Hematocrit and mean corpuscular volume As shown in A and B of FIG. 5, the hematocrit (HCT) in SCD mice was significantly decreased compared to healthy control mice. Treatment of SCD mice with the hepcidin mimetic disclosed herein, such as Compound 46, resulted in a significant dose-dependent decrease in HCT. The mean corpuscular volume (MCV) in SCD mice was significantly increased compared to healthy control mice. Treatment of SCD mice with the hepcidin mimetic disclosed herein, such as Compound 46, resulted in a significant dose-dependent decrease in MCV compared to the vehicle group. 【0165】 Mean corpuscular hemoglobin amount, and mean corpuscular hemoglobin concentration As shown in A and B of FIG. 6, both the mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) in SCD mice were significantly lower compared to healthy control mice. Treatment of SCD mice with hepcidin mimetics disclosed herein, such as Compound 46, resulted in a significant decrease in MCH compared to vehicle control. Treatment of SCD mice with hepcidin mimetics disclosed herein, such as 2.5 mg / kg of Compound 46, resulted in a significant increase in MCHC compared to vehicle control. 【0166】 White blood cell count and lymphocyte count As shown in A and B of FIG. 7, the white blood cell (WBC) count and lymphocyte count in SCD mice were significantly increased compared to the healthy control. Treatment of SCD mice with hepcidin mimetics disclosed herein, such as Compound 46, resulted in a dose-dependent significant decrease in WBC and lymphocytes. 【0167】 Neutrophil count and monocyte count As shown in A and B of FIG. 8, the neutrophil count and monocyte count in SCD mice were significantly increased compared to healthy controls. Treatment of SCD mice with hepcidin mimetics disclosed herein, such as Compound 46, resulted in a dose-dependent significant decrease in neutrophil count. 【0168】 Total bilirubin in serum and lactate dehydrogenase in serum Total bilirubin in serum and lactate dehydrogenase in serum are hemolysis biomarkers. As shown in A and B of FIG. 9, lactate dehydrogenase (LDH) and total bilirubin in the serum of SCD mice were significantly higher compared to the healthy control, which reflects the degree of hemolysis. Treatment of SCD mice with hepcidin mimetics disclosed herein, such as Compound 46, significantly decreased both parameters in a dose-dependent manner. 【0169】 Thus, hepcidin mimetic peptides may potentially be beneficial in reducing mean erythrocyte hemoglobin concentration, reducing RBC sickling, thereby improving hemodynamics and oxygen-carrying capacity, and preventing hemolysis and vaso-occlusion. 【0170】 Table 1 summarizes the hematological parameters obtained from the treatment trials. 【Table 2】 【0171】 Table 2 summarizes the serum chemistry results of the treatment trials. 【Table 3】 【0172】 Table 3 shows data on spleen weight, liver weight, spleen-to-body weight ratio, and liver-to-body weight ratio. 【Table 4】 【0173】 All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet are hereby incorporated by reference in their entirety. 【0174】 Specific embodiments of the invention have been described herein for purposes of illustration, but it will be well understood from the above that various modifications can be made without departing from the spirit and scope of the invention.

Claims

[Claim 1] A pharmaceutical product comprising a hepcidin analog or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating sickle cell disease in a subject requiring the treatment thereof, wherein the method comprises: Hepcidin mimetic or a pharmaceutically acceptable salt or solvate thereof, A pharmaceutical composition comprising a hepcidin mimetic or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. The pharmaceutical agent comprising administering the above. [Claim 2] The aforementioned hepcidin mimetic is given by formula I: R1-X-Y-R2 (I) [During the ceremony, R1 is a C1-C20 alkanoyl, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, or pGlu; R2 is NH ２ or OH; X is the amino acid sequence of formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (II) (In the formula, X1 is Glu, Asp, Ala, Ida, bhAsp, Leu, D-Asp, or absent; X2 is Thr, Ala, or D-Thr; X3 is His, Lys, D-His, or Lys; X4 is Phe, Ala, Dpa, or D-Phe; X5 is Pro, Gly, Arg, Lys, Ala, D-Pro, or bhPro; X6 is Cys, Ile, Arg, Lys, D-Ile, or D-Cys; X7 is Ile, Cys, Leu, Val, Phe, D-Ile, or D-Cys; X8 is Lys, Ile, Arg, Phe, Gln, Glu, Val, Leu, or D-Ile; X9 is either Phe or bhPhe; X10 is absent, Lys, or Phe. And; If Y is absent, then X7 is Ile; Y is the amino acid sequence of formula III: Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (III) (In the formula, Y1 is Glu, Gly, Cys, Ala, Phe, Pro, Lys, D-Pro, Val, Ser, or absent; Y2 is Pro, Ala, Cys, Gly, or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp, or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr, or absent; Y5 is Lys, Met, Arg, Ala, or absent; Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val, or absent; Y7 is Absence, Trp, Lys, Gly, Ala, Ile, or Val; Y8 is Cys, Val, Thr, Gly, Met, Tyr, Ala, Glu, Lys, Asp, Arg, or absent; Y9 is absent, Cys, or Tyr; Y10 is Lys, Met, Arg, Tyr, or absent; Y11 is absent, Arg, Met, Cys, or Lys; Y12 is absent, Arg, Lys, or Ala; Y13 is absent, Arg, Cys, Lys, or Val; Y14 is absent, Arg, Lys, Pro, Cys, or Thr; Y15 is absent, Thr, or Arg. is] A peptide containing or having, or a pharmaceutically acceptable salt or solvate thereof; The peptide of formula I is optionally pegylated at R1, X, or Y; The amino acid side chains of the peptide are optionally conjugated to lipophilic substituents or polymeric moieties; The peptide of formula I optionally has a disulfide bond formed between the thiol groups of two cysteine ​​residues in the peptide; Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid, and bhPro is β-homoproline. The pharmaceutical product according to claim 1. [Claim 3] The pharmaceutical product according to claim 2, wherein R1 is isovaleric acid, hydrogen, isobutyric acid, or acetyl. [Claim 4] X is the amino acid sequence of formula IV: X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (IV) [During the ceremony, X1 is Glu, Asp, Ida, bhAsp, or absent; X4 is either Phe or Dpa; X5 is either Pro or bhPro; X6 is Cys, Ile, or Arg; X7 is Ile, Cys, Leu, or Val; X8 is Lys, Ile, Glu, Phe, Glun, or Arg; X10 is absent or Lys. The pharmaceutical product according to claim 2 or 3, comprising or consisting of the following. [Claim 5] X is the amino acid sequence of formula V: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (V) [During the ceremony, X1 is Glu, Asp, Ida, bhAsp, or absent; X4 is either Phe or Dpa; X5 is either Pro or bhPro; X8 is Lys, Ile, Glu, Phe, Glun, or Arg; X10 is absent or Lys. The pharmaceutical product according to claim 2 or 3, comprising or consisting of the following. [Claim 6] The peptide is given by formula VI: R １ -X-Y-R ２ (VI) [During the ceremony, R １ These are isovaleric acid, hydrogen, isobutyric acid, or acetyl; R ２ NH ２ or OH; X is the amino acid sequence of formula VII: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (VII) (In the formula, X1 is Glu, Asp, Ida, bhAsp, or absent; X4 is either Phe or Dpa; X5 is either Pro or bhPro; X8 is Lys, Ile, Glu, Phe, Glun, or Arg; X10 is absent or Lys. And; Y is the amino acid sequence of formula VIII: Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (VIII) (In the formula, Y1 is Glu, Gly, Val, or Lys; Y3 is either Arg or Lys; Y5 is either Lys or Arg; Y6 is Gly, Ser, Lys, Ile, or Arg; Y7 is absent or trp; Y8 is absent, Val, Thr, Asp, or Glu; Y10 is either Lys or absent. is] or having a pharmaceutically acceptable salt or solvate thereof; The peptide optionally has a disulfide bond formed between the thiol groups of two cysteine ​​residues in the peptide; The aforementioned peptide, R １ , optionally pegged in X or Y; The amino acid side chains of the peptide are optionally conjugated to lipophilic substituents or polymeric moieties; Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid, and bhPro is β-homoproline. The pharmaceutical product according to claim 2. [Claim 7] The aforementioned hepcidin mimetic, Isovaleric acid-ETHFPCI (K(IsoGlu_Palm))FEPRSKGCK-NH 2 (Compound 46; SEQ ID NO: 46); Isovaleric acid-DTHFPICIFGPRSKGWVC-NH ２ (Compound 1; SEQ ID NO: 1); Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH ２ (Compound 2; SEQ ID NO: 2); Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH ２ (Compound 3; SEQ ID NO: 3); Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH ２ (Compound 4; Sequence ID No. 4); Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH ２ (Compound 5; SEQ ID NO: 5); Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH ２ (Compound 6; SEQ ID NO: 6); Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH ２ (Compound 7; SEQ ID NO: 7); Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH ２ (Compound 8; Sequence ID No. 8); Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVC-NH ２ (Compound 9; Sequence ID No. 9); Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVC-NH ２ (Compound 10; SEQ ID NO: 10); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH ２ (Compound 11; SEQ ID NO: 11); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH ２ (Compound 12; SEQ ID NO: 12); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH ２ (Compound 13; SEQ ID NO: 13); Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH ２ (Compound 14; SEQ ID NO: 14); Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH ２ (Compound 15; SEQ ID NO: 15); Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH ２ (Compound 16; SEQ ID NO: 16); Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH ２ (Compound 17; SEQ ID NO: 17); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))NH ２ (Compound 18; SEQ ID NO: 18); Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH ２ (Compound 19; SEQ ID NO: 19); Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH ２ (Compound 20; SEQ ID NO: 20); Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH ２ (Compound 21; SEQ ID NO: 21); Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH ２ (Compound 22; SEQ ID NO: 22); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH ２ (Compound 23; SEQ ID NO: 23); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH ２ (Compound 24; SEQ ID NO: 24); Iso-glucosamine-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH ２ (Compound 25; Allocation number 25); Isogibric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-NH ２ (Compound 26; Allocation number 26); Isogibric acid-DTHFPCIKFEP (K(isoGlu-Palm))SKGCK-NH ２ (Compound 27; Allocation number 27); Isovaleric acid-DTHFPCIKFEP (K(isoGlu-Palm))SKGWECK-NH ２ (Compound 28; Sequence ID No. 28); Iso-glucosamine-DTHFPCIKFEPRS (K(isoGlu-Palm))GCK-NH ２ (Compound 29; Allocation number 29); Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-NH ２ (Compound 30; Sequence ID No. 30); Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-NH ２ (Compound 31; SEQ ID NO: 31); Isovaleric acid-DTHFPCI-K(Dap-Palm)-FEPRSKGCK-NH ２ (Compound 32; SEQ ID NO: 32); Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH ２ (Compound 33; SEQ ID NO: 33); Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH ２ (Compound 34; SEQ ID NO: 34); Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH ２ (Compound 35; Sequence ID No. 35); Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH ２ (Compound 36; SEQ ID NO: 36); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-NH ２ (Compound 37; Sequence ID No. 37); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH ２ (Compound 38; Sequence ID No. 38); Isovaleric acid-DTHFPCIKF(K(PEG11-Palm))PRSK[Sar]CK-NH ２ (Compound 39; Sequence ID No. 39); Isovaleric acid-DTHFPCIKF-NH ２ (Compound 40; Sequence ID No. 40); Hy-DTHFPCIKF-NH ２ (Compound 41; SEQ ID NO: 41); Isovaleric acid-DTHFPCIIF-NH ２ (Compound 42; SEQ ID NO: 42); Hy-DTHFPCIIKF-NH ２ (Compound 43; SEQ ID NO: 43); Isovaleric acid-DTKFPCIIF-NH ２ (Compound 44; Sequence ID No. 44); and Hy-DTKFPCIIF-NH ２ (Compound 45; Sequence ID No. 45) A peptide comprising a sequence or structure selected from, or a pharmaceutically acceptable salt or solvate thereof; The peptide optionally has a disulfide bond formed between the thiol groups of two cysteine ​​residues in the peptide. The pharmaceutical product according to claim 1. [Claim 8] The aforementioned peptide Isovaleric acid-ETHFPCI(K(IsoGlu_Palm))FEPRSKGCK-NH2 (Compound 46; SEQ ID NO: 46); or Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH ２ (Compound 2; SEQ ID NO: 2); or Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH ２ (Compound 3; SEQ ID NO: 3); or Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH ２ (Compound 7; Sequence ID No. 7); or Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH ２ (Compound 8; Sequence ID No. 8); or Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH ２ (Compound 11; SEQ ID NO: 9); or Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH ２ (Compound 14; SEQ ID NO: 14); or Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH ２ (Compound 15; SEQ ID NO: 15); or Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH ２ (Compound 16; SEQ ID NO: 16); or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH ２ (Compound 18; SEQ ID NO: 18); or Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH ２ (Compound 19; SEQ ID NO: 19); or Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH ２ (Compound 20; Sequence ID No. 20); or Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH ２ (Compound 21; SEQ ID NO: 21); or Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH ２ (Compound 22; SEQ ID NO: 22); or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH ２ (Compound 23; SEQ ID NO: 23); or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH ２ (Compound 24; SEQ ID NO: 24); or Isovaleric acid-DTHFPCI (K(isoGlu-Palm))FEPRSKGCK-NH ２ (Compound 25; SEQ ID NO: 25); or Isovaleric acid-DTHFPCIKF (K(isoGlu-Palm))PRSKGCK-NH ２ (Compound 26; SEQ ID NO: 26); or Isovaleric acid-DTHFPCIKFEP (K(isoGlu-Palm))SKGCK-NH ２ (Compound 27; Sequence ID No. 27); or Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH ２ (Compound 28; Sequence ID No. 28); or Isovaleric acid-DTHFPCI(K(Dap-Palm))FEPRSKGCK-NH ２ (Compound 32; SEQ ID NO: 32); or Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH ２ (Compound 34; Sequence ID No. 34) The pharmaceutical product according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each peptide optionally has a disulfide bond formed between the thiol groups of two cysteine ​​residues in the peptide. [Claim 9] The aforementioned peptide (a) 【Chemistry 1】 or (b) 【Chemistry 2】 or (c) 【Transformation 3】 or (d) 【Chemistry 4】 or (e) 【Transformation 5】 or (f) 【Transformation 6】 The pharmaceutical product according to claim 1, wherein the amino acid is selected from a pharmaceutically acceptable salt or solvate thereof, and the amino acid is an L-amino acid. [Claim 10] The pharmaceutical product according to claim 1, wherein the hepcidin mimetic or peptide is administered subcutaneously to the subject. [Claim 11] The pharmaceutical product according to claim 1, wherein the effective dose comprises a dose in the range of about 0.1 mg / kg body weight to about 100 mg / kg body weight, and the subject is optionally administered different doses at different intervals during the course of treatment. [Claim 12] The pharmaceutical product according to claim 1, wherein the subject is administered the effective amount of the hepcidin mimetic about once a week, about twice a week, or about three times a week for at least some period of time during the course of the treatment. [Claim 13] The aforementioned hepcidin mimetic is given by formula: (a) 【Transformation 7】 or (b) 【Transformation 8】 The pharmaceutical product according to claim 1, which is a peptide having, or a pharmaceutically acceptable salt or solvate thereof. [Claim 14] The aforementioned hepcidin mimetic is given by formula: 【Chemistry 9】 The pharmaceutical product according to claim 1, which is a peptide having, or a pharmaceutically acceptable salt or solvate thereof. [Claim 15] The pharmaceutical product according to claim 1, wherein the sickle cell disease is sickle cell anemia (HbSS), HbSβ0 thalassemia, HbSβ+ thalassemia, or hemoglobin SC disease (HbSC). [Claim 16] The pharmaceutical product according to claim 1, wherein the subject has a decrease in the number of red blood cells. [Claim 17] The pharmaceutical product according to claim 1, wherein the subject has a decrease in hemoglobin count. [Claim 18] The pharmaceutical product according to claim 1, wherein the subject has a reduction in hematocrit. [Claim 19] The pharmaceutical product according to claim 1, wherein the subject has a decrease in the number of lymphocytes.

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