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High-throughput screening of small molecules identifies hepcidin antagonists
Eileen Fung1, Priscilla Sugianto, Jason Hsu
1Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Molecular Pharmacology
|January 8, 2013
Summary
Researchers identified fursultiamine, an FDA-approved drug, as a potent hepcidin antagonist in vitro. This discovery offers a potential new therapeutic strategy for anemia of inflammation and other iron-related disorders by targeting the hepcidin-ferroportin interaction.
Area of Science:
- Biochemistry
- Pharmacology
- Hematology
Background:
- Anemia of inflammation (AI) is prevalent in chronic diseases, with limited treatment options.
- Hepcidin, an iron regulatory hormone, is a key factor in AI pathogenesis.
- Current AI treatments have limitations and potential adverse effects.
Purpose of the Study:
- To identify novel hepcidin antagonists for treating AI and related iron disorders.
- To explore therapeutic strategies targeting hepcidin excess.
Main Methods:
- Developed a cell-based screen to identify hepcidin antagonists from a library of 70,000 small molecules.
- Investigated the mechanism of action of identified compounds on ferroportin.
- Assessed the efficacy of fursultiamine in vitro and in vivo.
Main Results:
- Identified 14 hepcidin antagonists, including fursultiamine, a thiamine derivative.
- Fursultiamine directly blocked hepcidin binding to ferroportin by targeting the C326 thiol residue.
- Fursultiamine prevented hepcidin-induced ferroportin degradation in vitro, maintaining iron export.
- Thiamine and benfotiamine did not antagonize hepcidin's effects.
- In vivo, fursultiamine's efficacy was limited due to rapid metabolism.
Conclusions:
- Fursultiamine is a potent in vitro hepcidin antagonist.
- Fursultiamine's mechanism involves direct interaction with ferroportin.
- The findings suggest fursultiamine as a template for developing new drugs targeting the hepcidin-ferroportin pathway for AI treatment.
