Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase

S. J. Kim, J. H. Kim, J. M. Sun, M. G. Kim, Jong-Won Oh

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Summary. Hepatitis C virus (HCV) infection is a serious threat to human health worldwide. In spite of the continued search for specific and effective anti-HCV therapies, the rapid emergence of drug-resistance variants has been hampering the development of anti-HCV drugs designed to target viral enzymes. Targeting host factors has therefore emerged as an alternative strategy offering the potential to circumvent the ever-present complication of drug resistance. We previously identified protein kinase C-related kinase 2 (PRK2) as a cellular kinase that phosphorylates the HCV RNA-dependent RNA polymerase (RdRp). Here, we report the anti-HCV activity of HA1077, also known as fasudil, and Y27632, which blocks HCV RdRp phosphorylation by suppressing PRK2 activation. Treatment of a Huh7 cell line, stably expressing a genotype 1b HCV subgenomic replicon RNA, with 20 μm each of HA1077 and Y27632 reduced the HCV RNA level by 55% and 30%, respectively. A combination of the inhibitors with 100 IU/mL interferon α (IFN-α) significantly potentiated the anti-HCV drug activities resulting in approximately a 2-log10 viral RNA reduction. We also found that IFN-α does not activate PRK2 as well as its upstream kinase PDK1 in HCV-replicating cells. Furthermore, treatment of HCV-infected cells with 20 μm each of HA1077 and Y27632 reduced the levels of intracellular viral RNA by 70% and 92%, respectively. Taken together, the results identify PRK2 inhibitors as potential antiviral drugs that act by suppressing HCV replication via inhibition of viral RNA polymerase phosphorylation.

Original languageEnglish
Pages (from-to)697-704
Number of pages8
JournalJournal of Viral Hepatitis
Volume16
Issue number10
DOIs
Publication statusPublished - 2009 Oct 1

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Replication Protein C
Viral RNA
DNA-Directed RNA Polymerases
Virus Replication
Hepacivirus
Phosphorylation
RNA Replicase
Drug Resistance
Interferons
protein kinase C kinase
Phosphotransferases
RNA
Replicon
Virus Diseases
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Infectious Diseases
  • Virology

Cite this

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title = "Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase",
abstract = "Summary. Hepatitis C virus (HCV) infection is a serious threat to human health worldwide. In spite of the continued search for specific and effective anti-HCV therapies, the rapid emergence of drug-resistance variants has been hampering the development of anti-HCV drugs designed to target viral enzymes. Targeting host factors has therefore emerged as an alternative strategy offering the potential to circumvent the ever-present complication of drug resistance. We previously identified protein kinase C-related kinase 2 (PRK2) as a cellular kinase that phosphorylates the HCV RNA-dependent RNA polymerase (RdRp). Here, we report the anti-HCV activity of HA1077, also known as fasudil, and Y27632, which blocks HCV RdRp phosphorylation by suppressing PRK2 activation. Treatment of a Huh7 cell line, stably expressing a genotype 1b HCV subgenomic replicon RNA, with 20 μm each of HA1077 and Y27632 reduced the HCV RNA level by 55{\%} and 30{\%}, respectively. A combination of the inhibitors with 100 IU/mL interferon α (IFN-α) significantly potentiated the anti-HCV drug activities resulting in approximately a 2-log10 viral RNA reduction. We also found that IFN-α does not activate PRK2 as well as its upstream kinase PDK1 in HCV-replicating cells. Furthermore, treatment of HCV-infected cells with 20 μm each of HA1077 and Y27632 reduced the levels of intracellular viral RNA by 70{\%} and 92{\%}, respectively. Taken together, the results identify PRK2 inhibitors as potential antiviral drugs that act by suppressing HCV replication via inhibition of viral RNA polymerase phosphorylation.",
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Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase. / Kim, S. J.; Kim, J. H.; Sun, J. M.; Kim, M. G.; Oh, Jong-Won.

In: Journal of Viral Hepatitis, Vol. 16, No. 10, 01.10.2009, p. 697-704.

Research output: Contribution to journalArticle

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AU - Kim, J. H.

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