Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy.
10.1007/s13238-018-0521-z
- Author:
Lin CAO
1
;
Jizheng CHEN
2
;
Yaxin WANG
1
;
Yuting YANG
3
;
Jie QING
4
;
Zihe RAO
1
;
Xinwen CHEN
5
;
Zhiyong LOU
6
Author Information
1. College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
2. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
3. Beijing No. 166 High School, Beijing, 100006, China.
4. School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University, Beijing, 100084, China.
5. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China. chenxw@wh.iov.cn.
6. School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University, Beijing, 100084, China. louzy@mail.tsinghua.edu.cn.
- Publication Type:Journal Article
- Keywords:
HCV;
antiviral drug;
entry;
serotonin 2A receptor
- From:
Protein & Cell
2019;10(3):178-195
- CountryChina
- Language:English
-
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-HTR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HTR and clinically available 5-HTR 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-HTR 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.
