Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase

Lee F. Peng, Esperance A.K. Schaefer, Nicole Maloof, Andrew Skaff, Andrew Berical, Craig A. Belon, Julie A. Heck, Wenyu Lin, David N. Frick, Todd M. Allen, Henry M. Miziorko, Stuart L. Schreiber, Raymond T. Chung

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background. Hepatitis C virus (HCV) chronically infects >170 million persons worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. The identification of more effective and better-tolerated agents for treating HCV is a high priority. We have reported elsewhere the discovery of the anti-HCV compound ceestatin using a high-throughput screen of a small molecule library. Methods. To identify host or viral protein targets in an unbiased fashion, we performed affinity chromatography, using tandem liquid chromatography/mass spectrometry to identify specific potential targets. Results. Ceestatin binds to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase and irreversibly inhibits HMG-CoA synthase in a dose-dependent manner. Ceestatin's anti-HCV effects are reversed by addition of HMG-CoA, mevalonic acid, or geranylgeraniol. Treatment with small interfering RNA against HMG-CoA synthase led to a substantial reduction in HCV replication, further validating HMG-CoA synthase as an enzyme essential for HCV replication. Conclusions. Ceestatin therefore exerts its anti-HCV effects through inhibition of HMG-CoA synthase. It may prove useful as an antiviral agent, as a probe to study HCV replication, and as a cholesterol-lowering agent. The logical stepwise process employed to discover the mechanism of action of ceestatin can serve as a general experimental strategy to uncover the targets on which novel uncharacterized anti-HCV compounds act.

Original languageEnglish (US)
Pages (from-to)609-616
Number of pages8
JournalJournal of Infectious Diseases
Volume204
Issue number4
DOIs
StatePublished - Aug 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Peng, L. F., Schaefer, E. A. K., Maloof, N., Skaff, A., Berical, A., Belon, C. A., Heck, J. A., Lin, W., Frick, D. N., Allen, T. M., Miziorko, H. M., Schreiber, S. L., & Chung, R. T. (2011). Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase. Journal of Infectious Diseases, 204(4), 609-616. https://doi.org/10.1093/infdis/jir303