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Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase.
Peng, Lee F; Schaefer, Esperance A K; Maloof, Nicole; Skaff, Andrew; Berical, Andrew; Belon, Craig A; Heck, Julie A; Lin, Wenyu; Frick, David N; Allen, Todd M; Miziorko, Henry M; Schreiber, Stuart L; Chung, Raymond T.
Afiliação
  • Peng LF; Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
J Infect Dis ; 204(4): 609-16, 2011 Aug 15.
Article em En | MEDLINE | ID: mdl-21791663
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Hepacivirus / Compostos Bicíclicos Heterocíclicos com Pontes / Hidroximetilglutaril-CoA Sintase / Lactonas Limite: Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Hepacivirus / Compostos Bicíclicos Heterocíclicos com Pontes / Hidroximetilglutaril-CoA Sintase / Lactonas Limite: Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article