TY - JOUR
T1 - Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes
AU - Chamoun-Emanuelli, Ana M.
AU - Pecheur, Eve Isabelle
AU - Simeon, Rudo L.
AU - Huang, Da
AU - Cremer, Paul S.
AU - Chena, Zhilei
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
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U2 - 10.1128/AAC.02593-12
DO - 10.1128/AAC.02593-12
M3 - Article
C2 - 23529728
AN - SCOPUS:84877850427
SN - 0066-4804
VL - 57
SP - 2571
EP - 2581
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 6
ER -