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
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