2-octynoic acid inhibits hepatitis C virus infection through activation of AMP-activated protein kinase

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 showe...

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Bibliographic Details
Published in:PloS one 2013-05, Vol.8 (5), p.e64932
Main Authors: Yang, Darong, Xue, Binbin, Wang, Xiaohong, Yu, Xiaoyan, Liu, Nianli, Gao, Yimin, Liu, Chen, Zhu, Haizhen
Format: Article
Language:English
Subjects:
Accumulation
Acetyl-CoA carboxylase
Acids
Activation
AMP
AMP-activated protein kinase
AMP-Activated Protein Kinases - metabolism
Antiviral activity
Antiviral Agents - pharmacology
Biology
Cell culture
Cell Line
Chronic infection
Cytotoxicity
Disease prevention
Drug development
Drug resistance
Enzyme Activation - drug effects
Fatty acids
Fatty Acids, Monounsaturated - pharmacology
Gastroenterology
Gene expression
Gene Expression Regulation - drug effects
Genomes
Hepacivirus - drug effects
Hepatitis
Hepatitis B
Hepatitis C
Hepatitis C - genetics
Hepatitis C - metabolism
Hepatocytes
Hospitals
Humans
Immune response
Immune system
Infections
Innate immunity
Interferon
Interferon Regulatory Factors - genetics
Intracellular
Kinases
Laboratories
Lipid Metabolism - drug effects
Lipids
Liver cancer
Medical research
Medicine
MicroRNAs
MicroRNAs - genetics
miRNA
Proteins
Replication
Ribonucleic acid
RNA
RNA viruses
RNA-mediated interference
Toxicity
Viral infections
Virus Replication - drug effects
Viruses
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0064932