title: Minihepcidins are rationally designed  small peptides that mimic hepcidin activity  in mice and may be useful for the treatment  of iron overload.
abstract: Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.
authors: Department of Pathology, UCLA, Los Angeles, California, USA.
authors: Gloria C
authors: GC
authors: Preza
authors: Piotr
authors: P
authors: Ruchala
authors: Rogelio
authors: R
authors: Pinon
authors: Emilio
authors: E
authors: Ramos
authors: Bo
authors: B
authors: Qiao
authors: Michael A
authors: MA
authors: Peralta
authors: Shantanu
authors: S
authors: Sharma
authors: Alan
authors: A
authors: Waring
authors: Tomas
authors: T
authors: Ganz
authors: Elizabeta
authors: E
authors: Nemeth
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000819:agonists* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics; D003198:Computer Simulation; D003545:Cysteine / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D064451:Hepcidins; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007501:Iron / Q000097:blood; D019190:Iron Overload / Q000188:drug therapy*; D008099:Liver / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D013329:Structure-Activity Relationship; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D010446:Peptide Fragments; D000098742:Ferroportin; D007501:Iron; D003545:Cysteine