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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2009-1-23
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pubmed:abstractText |
HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-11110665,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-11152517,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-11312331,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-11583749,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-12324553,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-12438626,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-12545532,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-15155230,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-15561857,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-15561861,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-15588095,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16087668,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16107835,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16149085,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16375756,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16407182,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16448708,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16641454,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16787301,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16787302,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16905788,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-16940072,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17024179,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17030169,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17067816,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17196931,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17402724,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-17408662,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-18086851,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-18285474,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-18559648,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-9305674,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-9385865,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18936191-9756471
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Benzofurans,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Directed DNA Polymerase,
http://linkedlifedata.com/resource/pubmed/chemical/Interferons,
http://linkedlifedata.com/resource/pubmed/chemical/N-(3-amino-1-(cyclobutylmethyl)-2,3-...,
http://linkedlifedata.com/resource/pubmed/chemical/Proline,
http://linkedlifedata.com/resource/pubmed/chemical/Protease Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Viral,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1098-6596
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
401-11
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:18936191-Antiviral Agents,
pubmed-meshheading:18936191-Benzofurans,
pubmed-meshheading:18936191-Cell Line,
pubmed-meshheading:18936191-Cloning, Molecular,
pubmed-meshheading:18936191-DNA-Directed DNA Polymerase,
pubmed-meshheading:18936191-Drug Resistance, Viral,
pubmed-meshheading:18936191-Electroporation,
pubmed-meshheading:18936191-Genetic Variation,
pubmed-meshheading:18936191-Hepacivirus,
pubmed-meshheading:18936191-Humans,
pubmed-meshheading:18936191-Interferons,
pubmed-meshheading:18936191-Mutagenesis,
pubmed-meshheading:18936191-Mutation,
pubmed-meshheading:18936191-Proline,
pubmed-meshheading:18936191-Protease Inhibitors,
pubmed-meshheading:18936191-RNA, Viral,
pubmed-meshheading:18936191-Replicon,
pubmed-meshheading:18936191-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:18936191-Sulfonamides
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pubmed:year |
2009
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pubmed:articleTitle |
Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
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pubmed:affiliation |
Wyeth Research, Pearl River, NY 10965, USA. flintm@wyeth.com
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