【摘 要】
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Hepatitis C virus (HCV) is a leading cause of liver disease worldwide.Although several HCV protease/polymerase inhibitors were recently approved by U.S.FDA,the
【机 构】
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College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin
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Hepatitis C virus (HCV) is a leading cause of liver disease worldwide.Although several HCV protease/polymerase inhibitors were recently approved by U.S.FDA,the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance.Viral entry is an essential target step for antiviral development,but FDA-approved HCV entry inhibitor remains exclusive.Here we identify serotonin 2A receptor (5-HT2AR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy.The silencing of 5-HT2AR and clinically available 5-HT2AR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process.The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1).Moreover,phenoxybenzamine (PBZ),an FDA-approved 5-HT2AR antagonist,inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs.The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice.Our results not only expand the understanding of HCV entry,but also present a promising target for the invention of HCV entry inhibitor.
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