Abstract
Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Crystallography, X-Ray
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Drug Resistance, Viral
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HIV Infections / drug therapy
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HIV Infections / virology*
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HIV Protease / chemistry
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HIV Protease / genetics*
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HIV Protease / metabolism
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HIV Protease Inhibitors / chemistry*
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HIV Protease Inhibitors / pharmacology
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HIV-1 / chemistry
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HIV-1 / drug effects*
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HIV-1 / enzymology*
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HIV-1 / genetics
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Humans
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Models, Molecular
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Mutagenesis, Insertional*
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Organophosphonates / analysis
Substances
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HIV Protease Inhibitors
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Organophosphonates
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HIV Protease
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p16 protease, Human immunodeficiency virus 1