ArticleProtein science : a publication of the Protein Society2005
Structural analysis of an HIV-1 protease I47A mutant resistant to the protease inhibitor lopinavir.
Article in Protein science : a publication of the Protein Society, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 45 citations in OpenAlex.
- 2022 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2022Article
- Different Mutation Tolerance of Lentiviral (HIV-1) and Deltaretroviral (BLV and HTLV) Protease Precursors.Viruses · 2022Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
- Molecular dynamics simulation in virus research.Frontiers in microbiology · 2012Article
- 2011 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2011Review
- Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings.AIDS research and treatment · 2011Article
- HIV-1 protease mutations and protease inhibitor cross-resistance.Antimicrobial agents and chemotherapy · 2010Article
- Current and Novel Inhibitors of HIV Protease.Viruses · 2009Article
- Virological response to highly active antiretroviral therapy in patients infected with human immunodeficiency virus type 2 (HIV-2) and in patients dually infected with HIV-1 and HIV-2 in the Gambia and emergence of drug-resistant variants.Journal of clinical microbiology · 2009Article
- Enzymatic and structural analysis of the I47A mutation contributing to the reduced susceptibility to HIV protease inhibitor lopinavir.Protein science : a publication of the Protein Society · 2008Article
- Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region.Journal of virology · 2008Article
- In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.Antimicrobial agents and chemotherapy · 2007Article
- X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir.Journal of virology · 2007Article
- Review
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Authors and funding
4 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
We have identified a rare HIV-1 protease (PR) mutation, I47A, associated with a high level of resistance to the protease inhibitor lopinavir (LPV) and with hypersusceptibility to the protease inhibitor saquinavir (SQV). The I47A mutation was found in 99 of 112,198 clinical specimens genotyped after LPV became available in late 2000, but in none of 24,426 clinical samples genotyped from 1998 to October 2000. Phenotypic data obtained for five I47A mutants showed unexpected resistance to LPV (86- to >110-fold) and hypersusceptibility to SQV (0.1- to 0.7-fold). Molecular modeling and energy calculations for these mutants using our structural phenotyping methodology showed an increase in the binding energy of LPV by 1.9-3.1 kcal/mol with respect to the wild type complex, corresponding to a 20- to >100-fold decrease in binding affinity, consistent with the observed high levels of LPV resistance. In the WT PR-LPV complex, the Ile 47 side chain is positioned close to the phenoxyacetyl moiety of LPV and its van der Waals interactions contribute significantly to the ligand binding. These interactions are lost for the smaller Ala 47 residue. Calculated binding energy changes for SQV ranged from -0.4 to -1.2 kcal/mol. In the mutant I47A PR-SQV complexes, the PR flaps are packed more tightly around SQV than in the WT complex, resulting in the formation of additional hydrogen bonds that increase binding affinity of SQV consistent with phenotypic hypersusceptibility. The emergence of mutations at PR residue 47 strongly correlates with increasing prescriptions of LPV (Spearman correlation r(s) = 0.96, P < .0001).
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