Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy
Received date: 05 Jan 2018
Accepted date: 06 Feb 2018
Published date: 21 Feb 2019
Copyright
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.
Key words: HCV; serotonin 2A receptor; entry; antiviral drug
Lin Cao , Jizheng Chen , Yaxin Wang , Yuting Yang , Jie Qing , Zihe Rao , Xinwen Chen , Zhiyong Lou . Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy[J]. Protein & Cell, 2019 , 10(3) : 178 -195 . DOI: 10.1007/s13238-018-0521-z
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