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

Protein & Cell

Yuting Yang¹  Zihe Rao²  Lin Cao²  Yaxin Wang²  Jie Qing³  Zhiyong Lou³  Jizheng Chen⁴  Xinwen Chen⁴ 

[1] Beijing No. 166 High School;College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai University;School of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua University;State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences;

关键词: HCV;    serotonin 2A receptor;    entry;    antiviral drug;   

DOI  :  10.1007/s13238-018-0521-z

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown