Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase.
PMID 21791663 · The Journal of infectious diseases · 2011 · DOI 10.1093/infdis/jir303
Authors: 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
Abstract
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. 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. 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.
Antiviral Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Chromatography, Affinity; Hepacivirus; Humans; Hydroxymethylglutaryl-CoA Synthase; Lactones; Mass Spectrometry; Protein Binding; RNA Interference; RNA, Small Interfering; Virus Replication
Cite
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. Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase. The Journal of infectious diseases (2011). PMID 21791663. DOI 10.1093/infdis/jir303.