Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes

Ana M. Chamoun-Emanuelli, Eve Isabelle Pecheur, Rudo L. Simeon, Da Huang, Paul S. Cremer, Zhilei Chena

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Despite recent progress in the development of direct-acting antiviral agents against hepatitisCvirus (HCV), more effective therapies are still urgently needed.Weand others previously identified three phenothiazine compounds as potentHCVentry inhibitors. In this study, we show that phenothiazines inhibitHCVentry at the step of virus-host cell fusion, by intercalating into cholesterol-rich domains of the target membrane and increasing membrane fluidity. Perturbation of the alignment/packing of cholesterol in lipid membranes likely increases the energy barrier needed for virus-host fusion. A screening assay based on the ability of molecules to selectively increase the fluidity of cholesterol-rich membranes was subsequently developed. One compound that emerged from the library screen, topotecan, is able to very potently inhibit the fusion of liposomes with cell culture-derivedHCV(HCVcc). These results yield new insights intoHCVinfection and provide a platform for the identification of newHCVinhibitors.

Original languageEnglish (US)
Pages (from-to)2571-2581
Number of pages11
JournalAntimicrobial agents and chemotherapy
Volume57
Issue number6
DOIs
StatePublished - Jun 2013

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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