RT Journal Article
SR Electronic
T1 High Throughput Screening of Small Molecules Identifies Hepcidin Antagonists
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.083428
DO 10.1124/mol.112.083428
A1 Eileen Fung
A1 Priscilla Sugianto
A1 Jason Hsu
A1 Robert Damoiseaux
A1 Tomas Ganz
A1 Elizabeta Nemeth
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/01/04/mol.112.083428.abstract
AB Anemia of inflammation (AI) is common in patients with infections, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities which are not always effective and can cause serious side effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, an FDA-approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis and degradation in vitro, and allowed continuous cellular iron export despite the presence of hepcidin, with IC50 in the sub-micromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely due to its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction.