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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2010-8-19
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pubmed:abstractText |
MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to approximately 13% of wt levels and increased resistance to MK-2048 to approximately 8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer "off" rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg(2+) binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-10384245,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-10557269,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-11997448,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-12069959,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-16525741,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-19129221,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-19265512,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-19759152,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20610719-9689049
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1098-5514
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
84
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
9210-6
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pubmed:dateRevised |
2011-7-25
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pubmed:meshHeading |
pubmed-meshheading:20610719-Amino Acid Substitution,
pubmed-meshheading:20610719-DNA Mutational Analysis,
pubmed-meshheading:20610719-Drug Resistance, Viral,
pubmed-meshheading:20610719-HIV Integrase,
pubmed-meshheading:20610719-HIV Integrase Inhibitors,
pubmed-meshheading:20610719-HIV-1,
pubmed-meshheading:20610719-Humans,
pubmed-meshheading:20610719-Models, Molecular,
pubmed-meshheading:20610719-Molecular Structure,
pubmed-meshheading:20610719-Mutagenesis, Site-Directed,
pubmed-meshheading:20610719-Mutation, Missense,
pubmed-meshheading:20610719-Protein Structure, Tertiary,
pubmed-meshheading:20610719-Pyrrolidinones,
pubmed-meshheading:20610719-Quinolones,
pubmed-meshheading:20610719-RNA, Viral,
pubmed-meshheading:20610719-Virus Replication
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pubmed:year |
2010
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pubmed:articleTitle |
Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor.
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pubmed:affiliation |
McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montréal, Quebec H3T 1E2, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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