Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload
Autor: | Gloria C. Preza, Bo Qiao, Rogelio Pinon, Piotr Ruchala, Tomas Ganz, Shantanu Sharma, Alan J. Waring, Michael A. Peralta, Emilio Ramos, Elizabeta Nemeth |
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Jazyk: | angličtina |
Rok vydání: | 2011 |
Předmět: |
inorganic chemicals
Models Molecular congenital hereditary and neonatal diseases and abnormalities Iron Overload Protein Conformation Transgene Iron Ferroportin Molecular Sequence Data Drug Evaluation Preclinical Pharmacology Mice Structure-Activity Relationship Hepcidins Oral administration Hepcidin hemic and lymphatic diseases Protein Interaction Mapping medicine Animals Humans Computer Simulation Amino Acid Sequence Cysteine Cation Transport Proteins Binding Sites biology medicine.diagnostic_test Chemistry nutritional and metabolic diseases General Medicine In vitro Peptide Fragments Biochemistry Amino Acid Substitution Liver Hereditary hemochromatosis Drug Design biology.protein Serum iron Mutagenesis Site-Directed Hydrophobic and Hydrophilic Interactions Research Article Antimicrobial Cationic Peptides |
Popis: | 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. |
Databáze: | OpenAIRE |
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