ArticleProceedings of the National Academy of Sciences of the United States of America2011
Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 70 citations in OpenAlex.
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.Journal of virology · 2026Article
- Molecular mechanisms of protease precursor autoprocessing of RNA viruses: a comprehensive review.Virology journal · 2026Review
- High-throughput screening and characterization of novel inhibitors targeting HIV-1 protease precursor autoprocessing.Scientific reports · 2025Article
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.bioRxiv : the preprint server for biology · 2025Article
- The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery.The Journal of biological chemistry · 2025Article
- Mechanism and Kinetics of HIV-1 Protease Activation.Viruses · 2024Review
- Unmasking the Conformational Stability and Inhibitor Binding to SARS-CoV-2 Main Protease Active Site Mutants and Miniprecursor.Journal of molecular biology · 2022Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Cryo-EM structure of the HIV-1 Pol polyprotein provides insights into virion maturation.Science advances · 2022Article
- Precursors of Viral Proteases as Distinct Drug Targets.Viruses · 2021Review
- Novel HIV PR inhibitors with C4-substituted bis-THF and bis-fluoro-benzyl target the two active site mutations of highly drug resistant mutant PRBiochemical and biophysical research communications · 2021Article
- Review
- Nanoscale flow cytometry reveals interpatient variability in HIV protease activity that correlates with viral infectivity and identifies drug-resistant viruses.Scientific reports · 2020Article
- Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.The FEBS journal · 2020Article
- Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design.ACS omega · 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
- Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20.Biochemical and biophysical research communications · 2019Article
- Diverse Folding Pathways of HIV-1 Protease Monomer on a Rugged Energy Landscape.Biophysical journal · 2019Article
- Inhibition of HIV Maturation via Selective Unfolding and Cross-Linking of Gag Polyprotein by a Mercaptobenzamide Acetylator.Journal of the American Chemical Society · 2019Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Self-cleavage at the N terminus of HIV-1 protease from the Gag-Pol precursor (autoprocessing) is crucial for stabilizing the protease dimer required for onset of mature-like catalytic activity, viral maturation, and propagation. Among nine clinical protease inhibitors (PIs), darunavir and saquinavir were the most effective in inhibiting wild-type HIV-1 group M precursor autoprocessing, with an IC(50) value of 1-2 μM, 3-5 orders of magnitude higher than their binding affinities to the corresponding mature protease. Accordingly, both group M and N precursor-PI complexes exhibit T(m)s 17-21 °C lower than those of the corresponding mature protease-PI complexes suggestive of markedly reduced stabilities of the precursor dimer-PI ensembles. Autoprocessing of group N (natural variant) and three group M precursors bearing 11-20 mutations associated with multidrug resistance was either weakly responsive or fully unresponsive to inhibitors at concentrations up to a practical limit of approximately 150 μM PI. This observation parallels decreases of up to 8 × 10(3)-fold (e.g., 5 pM to 40 nM) in the binding affinity of darunavir and saquinavir to mature multidrug resistant proteases relative to wild type, suggesting that inhibition of some of these mutant precursors will occur only in the high μM to mM range in extreme PI-resistance, which is an effect arising from coordinated multiple mutations. An extremely darunavir-resistant mutant precursor is more responsive to inhibition by saquinavir. These findings raise the questions whether clinical failure of PI therapy is related to lack of inhibition of autoprocessing and whether specific inhibitors can be designed with low-nM affinity to target autoprocessing.
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