2. Academic Validation
  3. Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy

Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy

  • Protein Cell. 2019 Mar;10(3):178-195. doi: 10.1007/s13238-018-0521-z.
Lin Cao 1 2,  Jizheng Chen 3,  Yaxin Wang 1 4 2,  Yuting Yang 5,  Jie Qing 2,  Zihe Rao 1 4 2,  Xinwen Chen 6,  Zhiyong Lou 7
Affiliations

Affiliations

  • 1 College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
  • 2 School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University, Beijing, 100084, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 4 National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 5 Beijing No. 166 High School, Beijing, 100006, China.
  • 6 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China. chenxw@wh.iov.cn.
  • 7 School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University, Beijing, 100084, China. louzy@mail.tsinghua.edu.cn.
PMID: 29542010 DOI: 10.1007/s13238-018-0521-z
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 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.

Keywords

HCV; antiviral drug; entry; serotonin 2A receptor.

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