title: 2-octynoic acid inhibits hepatitis C virus infection through activation of AMP-activated protein kinase.
abstract: Many chronic hepatitis C virus (HCV)-infected patients with current therapy do not clear the virus. It is necessary to find novel treatments. The effect of 2-octynoic acid (2-OA) on HCV infection in human hepatocytes was examined. The mechanism of 2-OA antiviral activity was explored. Our data showed that 2-OA abrogated lipid accumulation in HCV replicon cells and virus-infected hepatocytes. It suppressed HCV RNA replication and infectious virus production with no cytotoxicity to the host cells. 2-OA did not affect hepatitis B virus replication in HepG2.2.15 cells derived from HepG2 cells transfected with full genome of HBV. Further study demonstrated that 2-OA activated AMP-activated protein kinase (AMPK) and inhibited acetyl-CoA carboxylase in viral-infected cells. Compound C, a specific inhibitor of AMPK, inhibited AMPK activity and reversed the reduction of intracellular lipid accumulation and the antiviral effect of 2-OA. Knockdown of AMPK expression by RNA interference abolished the activation of AMPK by 2-OA and blocked 2-OA antiviral activity. Interestingly, 2-OA induced interferon-stimulated genes (ISGs) and inhibited microRNA-122 (miR-122) expression in virus-infected hepatocytes. MiR-122 overexpression reversed the antiviral effect of 2-OA. Furthermore, knockdown of AMPK expression reversed both the induction of ISGs and suppression of miR-122 by 2-OA, implying that activated AMPK induces the intracellular innate response through the induction of ISGs and inhibiting miR-122 expression. 2-OA inhibits HCV infection through regulation of innate immune response by activated AMPK. These findings reveal a novel mechanism by which active AMPK inhibits HCV infection. 2-OA and its derivatives hold promise for novel drug development for chronic hepatitis C.
authors.affiliation: Department of Molecular Medicine of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan Province, China.
authors.forename: Darong
authors.initials: D
authors.lastname: Yang
authors.forename: Binbin
authors.initials: B
authors.lastname: Xue
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yu
authors.forename: Nianli
authors.initials: N
authors.lastname: Liu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Gao
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005229:Fatty Acids, Monounsaturated; D050835:Interferon Regulatory Factors; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C060855:2-octynoic acid; D055372:AMP-Activated Protein Kinases