Premium
Suppression of hepatitis C virus replication by protein kinase C‐related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase
Author(s) -
Kim S.J.,
Kim J.H.,
Sun J.M.,
Kim M.G.,
Oh J.W.
Publication year - 2009
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/j.1365-2893.2009.01108.x
Subject(s) - hepatitis c virus , virology , kinase , viral replication , polymerase , rna , rna polymerase , interferon , rna dependent rna polymerase , subgenomic mrna , phosphorylation , biology , medicine , virus , enzyme , microbiology and biotechnology , biochemistry , gene
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 μ m 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‐log 10 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 μ m 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.