title: A Schisandra-Derived Compound Schizandronic Acid Inhibits Entry of Pan-HCV Genotypes into Human Hepatocytes.
abstract: Despite recent progress in the development of hepatitis C virus (HCV) inhibitors, cost-effective antiviral drugs, especially among the patients receiving liver transplantations, are still awaited. Schisandra is a traditional medicinal herb used to treat a range of liver disorders including hepatitis for thousands of years in China. To isolate the bioactive compounds of schisandra for the treatment of HCV infection, we screened a schisandra-extracts library and identified a tetracyclic triterpenoid, schizandronic acid (SZA), as a novel HCV entry inhibitor. Our findings suggested that SZA potently inhibited pan-HCV genotype entry into hepatoma cells and primary human hepatocytes without interfering virus binding on cell surface or internalization. However, virion-cell fusion process was impaired in the presence of SZA, along with the increased host membrane fluidity. We also found that SZA inhibited the spread of HCV to the neighboring cells, and combinations of SZA with interferon or telaprevir resulted in additive synergistic effect against HCV. Additionally, SZA diminished the establishment of HCV infection in vivo. The SZA target is different from conventional direct-acting antiviral agents, therefore, SZA is a potential therapeutic compound for the development of effective HCV entry inhibitors, especially for patients who need to prevent HCV reinfection during the course of liver transplantations.
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xi-Jing
authors.initials: XJ
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Virology, Medical Research Institute of Wuhan University and Department of Immunology and Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, 185 Donghu Road, Wuhan 430071, Hubei Province, China.
authors.forename: Xiao-Lian
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Jin
authors.affiliation: Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hai-Sheng
authors.initials: HS
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qing-Qiang
authors.initials: QQ
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Tang
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yong-Zhe
authors.initials: YZ
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology; D005838:Genotype; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000821:virology*; D022781:Hepatocytes; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D032141:Schisandra / Q000737:chemistry*; D014315:Triterpenes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D053585:Virus Attachment; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D004365:Drugs, Chinese Herbal; D009842:Oligopeptides; D014315:Triterpenes; C486464:telaprevir; D007372:Interferons