ArticleACS chemical biology2019
Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.
Article in ACS chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Conformational asymmetry of human immunodeficiency virus-1 protease flaps increases along the darunavir drug resistance pathway.Protein science : a publication of the Protein Society · 2026Article
- Fluorinated HIV-1 protease inhibitors containing chiral hydroxyethylbenzene and indanol as P2' ligands with potent activity against drug-resistant variants.European journal of medicinal chemistry · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
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- Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.Viruses · 2024Article
- Modeling and Analysis of HIV-1 Pol Polyprotein as a Case Study for Predicting Large Polyprotein Structures.International journal of molecular sciences · 2024Article
- HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues.European journal of medicinal chemistry · 2023Article
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- Evolving Mutational Buildup in HIV-1 Protease Shifts Conformational Dynamics to Gain Drug Resistance.Journal of chemical information and modeling · 2023Article
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- Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.eLife · 2023Article
- Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins.The journal of physical chemistry. B · 2022Article
- HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics.Journal of molecular graphics & modelling · 2022Article
- Prediction and molecular field view of drug resistance in HIV-1 protease mutants.Scientific reports · 2022Article
- The evolution of the HIV-1 protease folding stability.Virus evolution · 2022Article
- Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit.The Journal of infectious diseases · 2021Article
- Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.Journal of chemical theory and computation · 2021Article
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Drug resistance continues to be a growing global problem. The efficacy of small molecule inhibitors is threatened by pools of genetic diversity in all systems, including antibacterials, antifungals, cancer therapeutics, and antivirals. Resistant variants often include combinations of active site mutations and distal "secondary" mutations, which are thought to compensate for losses in enzymatic activity. HIV-1 protease is the ideal model system to investigate these combinations and underlying molecular mechanisms of resistance. Darunavir (DRV) binds wild-type (WT) HIV-1 protease with a potency of <5 pM, but we have identified a protease variant that loses potency to DRV 150 000-fold, with 11 mutations in and outside the active site. To elucidate the roles of these mutations in DRV resistance, we used a multidisciplinary approach, combining enzymatic assays, crystallography, and molecular dynamics simulations. Analysis of protease variants with 1, 2, 4, 8, 9, 10, and 11 mutations showed that the primary active site mutations caused ∼50-fold loss in potency (2 mutations), while distal mutations outside the active site further decreased DRV potency from 13 nM (8 mutations) to 0.76 μM (11 mutations). Crystal structures and simulations revealed that distal mutations induce subtle changes that are dynamically propagated through the protease. Our results reveal that changes remote from the active site directly and dramatically impact the potency of the inhibitor. Moreover, we find interdependent effects of mutations in conferring high levels of resistance. These mechanisms of resistance are likely applicable to many other quickly evolving drug targets, and the insights may have implications for the design of more robust inhibitors.
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