ArticleJournal of virology2009
Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.
Article in Journal of virology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 48 citations in OpenAlex.
- PLXFPred: interpretable cross-attention networks with hierarchical fusion of multi-modal features for predicting protein-ligand interactions and affinities.Bioinformatics (Oxford, England) · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Prediction and molecular field view of drug resistance in HIV-1 protease mutants.Scientific reports · 2022Article
- The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.Frontiers in molecular biosciences · 2022Article
- Precursors of Viral Proteases as Distinct Drug Targets.Viruses · 2021Review
- Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance.Viruses · 2020Article
- Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.The FEBS journal · 2020Article
- Structural and binding insights into HIV-1 protease and P2-ligand interactions through molecular dynamics simulations, binding free energy and principal component analysis.Journal of molecular graphics & modelling · 2019Article
- Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.ACS infectious diseases · 2019Article
- Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution.The Journal of biological chemistry · 2016Article
- Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance.Frontiers in microbiology · 2016Article
- The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops.Biochemistry and biophysics reports · 2015Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
- Structures of darunavir-resistant HIV-1 protease mutant reveal atypical binding of darunavir to wide open flaps.ACS chemical biology · 2014Article
- Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1.Antimicrobial agents and chemotherapy · 2013Article
- Evaluation of a benchtop HIV ultradeep pyrosequencing drug resistance assay in the clinical laboratory.Journal of clinical microbiology · 2013Article
- Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease.Antimicrobial agents and chemotherapy · 2012Article
- HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements.Biochemistry · 2012Article
- Enhancing protein backbone binding--a fruitful concept for combating drug-resistant HIV.Angewandte Chemie (International ed. in English) · 2012Review
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.