2-Octynoic Acid Inhibits Hepatitis C Virus Infection through Activation of AMP-Activated Protein Kinase

Darong Yang, Binbin Xue, Xiaohong Wang, Xiaoyan Yu, Nianli Liu, Yimin Gao, Chen Liu, Haizhen Zhu

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere64932
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 31 2013
Externally publishedYes

Fingerprint

AMP-activated protein kinase
AMP-Activated Protein Kinases
Hepatitis C virus
Virus Diseases
Viruses
Hepacivirus
Chemical activation
acids
infection
Antiviral Agents
interferons
Genes
MicroRNAs
microRNA
Interferons
chronic hepatitis C
hepatocytes
Hepatocytes
viruses
Chronic Hepatitis C

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Yang, Darong ; Xue, Binbin ; Wang, Xiaohong ; Yu, Xiaoyan ; Liu, Nianli ; Gao, Yimin ; Liu, Chen ; Zhu, Haizhen. / 2-Octynoic Acid Inhibits Hepatitis C Virus Infection through Activation of AMP-Activated Protein Kinase. In: PloS one. 2013 ; Vol. 8, No. 5.
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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.",
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2-Octynoic Acid Inhibits Hepatitis C Virus Infection through Activation of AMP-Activated Protein Kinase. / Yang, Darong; Xue, Binbin; Wang, Xiaohong; Yu, Xiaoyan; Liu, Nianli; Gao, Yimin; Liu, Chen; Zhu, Haizhen.

In: PloS one, Vol. 8, No. 5, e64932, 31.05.2013.

Research output: Contribution to journalArticle

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