Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy
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 dr...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2018-03-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1007/s13238-018-0521-z |
| _version_ | 1797714111336808448 |
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| author | Lin Cao Jizheng Chen Yaxin Wang Yuting Yang Jie Qing Zihe Rao Xinwen Chen Zhiyong Lou |
| author_facet | Lin Cao Jizheng Chen Yaxin Wang Yuting Yang Jie Qing Zihe Rao Xinwen Chen Zhiyong Lou |
| author_sort | Lin Cao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:47:05Z |
| format | Article |
| id | doaj.art-a87566591c214830bcb2b36643d3e0db |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T07:47:05Z |
| publishDate | 2018-03-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-a87566591c214830bcb2b36643d3e0db2023-09-02T20:53:38ZengOxford University PressProtein & Cell1674-800X1674-80182018-03-0110317819510.1007/s13238-018-0521-zIdentification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategyLin Cao0Jizheng Chen1Yaxin Wang2Yuting Yang3Jie Qing4Zihe Rao5Xinwen Chen6Zhiyong Lou7College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of SciencesCollege of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai UniversityBeijing No. 166 High SchoolSchool of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua UniversityCollege of Pharmacy & State Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of SciencesSchool of Medicine and Collaborative Innovation Center of Biotherapy, Tsinghua UniversityABSTRACT 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.http://link.springer.com/article/10.1007/s13238-018-0521-zHCVserotonin 2A receptorentryantiviral drug |
| spellingShingle | 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 Protein & Cell HCV serotonin 2A receptor entry antiviral drug |
| title | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy |
| title_full | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy |
| title_fullStr | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy |
| title_full_unstemmed | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy |
| title_short | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy |
| title_sort | identification of serotonin 2a receptor as a novel hcv entry factor by a chemical biology strategy |
| topic | HCV serotonin 2A receptor entry antiviral drug |
| url | http://link.springer.com/article/10.1007/s13238-018-0521-z |
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