Jizheng Chen
Yaxin Wang
Yuting Yang
Jie Qing
Zihe Rao
Xinwen Chen
Zhiyong Lou
1 College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China;
2 National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
4 School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University, Beijing 100084, China;
5 Beijing No. 166 High School, Beijing 100006, China
Received Date: 2018-01-05
Abstract
Abstract
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 FDAapproved 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.Keywords: HCV,
serotonin 2A receptor,
entry,
antiviral drug
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