Source:http://linkedlifedata.com/resource/pubmed/id/19243496
Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
10
|
pubmed:dateCreated |
2009-9-22
|
pubmed:abstractText |
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 microm 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 alpha (IFN-alpha) significantly potentiated the anti-HCV drug activities resulting in approximately a 2-log(10) viral RNA reduction. We also found that IFN-alpha does not activate PRK2 as well as its upstream kinase PDK1 in HCV-replicating cells. Furthermore, treatment of HCV-infected cells with 20 microm 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.
|
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-(5-Isoquinolinesulfonyl)-2-Methylp...,
http://linkedlifedata.com/resource/pubmed/chemical/Amides,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Directed RNA Polymerases,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Viral Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Y 27632,
http://linkedlifedata.com/resource/pubmed/chemical/fasudil,
http://linkedlifedata.com/resource/pubmed/chemical/protein kinase N
|
pubmed:status |
MEDLINE
|
pubmed:month |
Oct
|
pubmed:issn |
1365-2893
|
pubmed:author | |
pubmed:issnType |
Electronic
|
pubmed:volume |
16
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
697-704
|
pubmed:meshHeading |
pubmed-meshheading:19243496-1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine,
pubmed-meshheading:19243496-Amides,
pubmed-meshheading:19243496-Cell Line,
pubmed-meshheading:19243496-DNA-Directed RNA Polymerases,
pubmed-meshheading:19243496-Hepacivirus,
pubmed-meshheading:19243496-Hepatocytes,
pubmed-meshheading:19243496-Humans,
pubmed-meshheading:19243496-Interferon-alpha,
pubmed-meshheading:19243496-Phosphorylation,
pubmed-meshheading:19243496-Protein Kinase C,
pubmed-meshheading:19243496-Protein Kinase Inhibitors,
pubmed-meshheading:19243496-Pyridines,
pubmed-meshheading:19243496-Viral Proteins,
pubmed-meshheading:19243496-Virus Replication
|
pubmed:year |
2009
|
pubmed:articleTitle |
Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase.
|
pubmed:affiliation |
Department of Biotechnology, Yonsei University, Seoul, Korea.
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|