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Molecular Pharmacology

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Research ArticleArticle

High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists

Eileen Fung, Priscilla Sugianto, Jason Hsu, Robert Damoiseaux, Tomas Ganz and Elizabeta Nemeth
Molecular Pharmacology March 2013, 83 (3) 681-690; DOI: https://doi.org/10.1124/mol.112.083428
Eileen Fung
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Priscilla Sugianto
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Jason Hsu
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Robert Damoiseaux
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Tomas Ganz
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Elizabeta Nemeth
Department of Medicine (E.F., P.S., J.H., T.G., E.N.), Department of Pathology (T.G.), and California Nanosystems Institute (R.D.), David Geffen School of Medicine, University of California, Los Angeles, California
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Abstract

Anemia of inflammation (AI) is common in patients with infection, 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 that are not always effective and can cause serious adverse 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, a Food and Drug Administration (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 submicromolar 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 because of 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.

Footnotes

  • This research was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01 DK082717]; and the UCLA Pepper Center for Aging (Grant P30 AG028748).

  • dx.doi.org/10.1124/mol.112.083428.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received November 1, 2012.
  • Accepted January 4, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (3)
Molecular Pharmacology
Vol. 83, Issue 3
1 Mar 2013
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Research ArticleArticle

Identification of Hepcidin Antagonists

Eileen Fung, Priscilla Sugianto, Jason Hsu, Robert Damoiseaux, Tomas Ganz and Elizabeta Nemeth
Molecular Pharmacology March 1, 2013, 83 (3) 681-690; DOI: https://doi.org/10.1124/mol.112.083428

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Research ArticleArticle

Identification of Hepcidin Antagonists

Eileen Fung, Priscilla Sugianto, Jason Hsu, Robert Damoiseaux, Tomas Ganz and Elizabeta Nemeth
Molecular Pharmacology March 1, 2013, 83 (3) 681-690; DOI: https://doi.org/10.1124/mol.112.083428
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