Despite recent addition of direct acting antiviral agents to hepatitis C virus' (HCV) standard of care treatment, more effective and non-genotype based therapies are still urgently needed. Insight gained into HCV entry over the last few years has allowed for the discovery and development of inhibitors at different steps of viral uptake. We and others have recently identified phenothiazines as potent HCV entry inhibitors and determined that phenothiazines inhibit HCV-host cell fusion by intercalating into the host cholesterol-rich membrane domains and altering cell membrane fluidity. Due to the important role of cholesterol in virus-host fusion, perturbing the alignment/packing of cholesterol in lipid membranes likely increases the energy barrier needed for viral-membrane fusion. Based on this principle, we developed a high-throughput screening assay and identified multiple hits that increase the fluidity of cholesterol-rich membranes. Many of these hits exhibited anti-HCV property in cell culture. These results yield new insight into HCV's life cycle, provide a new platform for HCV inhibitor identification and a novel mode for suppressing HCV infection.

Phenothiazines inhibit HCV fusion by increasing fluidity of target cholesterol-rich membrane

245th National Meeting (2013)

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