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Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy
- Source :
- Protein & Cell, Vol 10, Iss 3, Pp 178-195 (2018)
- Publication Year :
- 2018
- Publisher :
- Oxford University Press, 2018.
-
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 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.
Details
- Language :
- English
- ISSN :
- 1674800X, 16748018, and 87566591
- Volume :
- 10
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- Protein & Cell
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.87566591c214830bcb2b36643d3e0db
- Document Type :
- article
- Full Text :
- https://doi.org/10.1007/s13238-018-0521-z