ArticleJournal of virology2010
In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors.
Article in Journal of virology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 93 citations in OpenAlex.
- Ligand Versatility and Resistance Mechanism of Monotherapy-Grade HIV-1 Protease Inhibitor GRL-142 Binding the Multidrug Resistant Variant p51: Insights from 1 μs MD Simulations.Journal of chemical information and modeling · 2026Article
- Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands.European journal of medicinal chemistry · 2025Article
- Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes.Bioorganic & medicinal chemistry letters · 2025Article
- Design of substituted tetrahydrofuran derivatives for HIV-1 protease inhibitors: synthesis, biological evaluation, and X-ray structural studies.Organic & biomolecular chemistry · 2024Article
- Structural and virologic mechanism of the emergence of resistance to MProceedings of the National Academy of Sciences of the United States of America · 2024Article
- GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants.Science advances · 2023Article
- Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.European journal of medicinal chemistry · 2023Article
- Article
- Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.Bioorganic & medicinal chemistry letters · 2023Article
- Article
- Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chemical communications (Cambridge, England) · 2022Review
- Highly Potent and Oral Macrocyclic Peptides as a HIV-1 Protease Inhibitor: mRNA Display-Derived Hit-to-Lead Optimization.ACS medicinal chemistry letters · 2022Article
- Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors.Communications biology · 2022Article
- Article
- Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease InhibitorsAntimicrobial agents and chemotherapy · 2022Article
- Single-Agent and Fixed-Dose Combination HIV-1 Protease Inhibitor Drugs in Fission Yeast (Pathogens (Basel, Switzerland) · 2021Article
- A synergy of activity, stability, and inhibitor-interaction of HIV-1 protease mutants evolved under drug-pressure.Protein science : a publication of the Protein Society · 2021Article
- Identification of an Antiretroviral Small Molecule That Appears To Be a Host-Targeting Inhibitor of HIV-1 Assembly.Journal of virology · 2021Article
- Benzothiazoles as potential antiviral agents.The Journal of pharmacy and pharmacology · 2020Review
- Design, Synthesis, and X-ray Studies of Potent HIV-1 Protease Inhibitors with P2-Carboxamide Functionalities.ACS medicinal chemistry letters · 2020Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1(MIX)) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1(MIX) became highly resistant to DRV, with a 50% effective concentration (EC(50)) ∼333-fold greater than that against HIV-1(NL4-3). HIV-1(MIX) at passage 51 (HIV-1(MIX(P51))) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1(MIX(P51)) was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1(MIX(P51)) had a resemblance with HIV-1(C) of the HIV-1(MIX) population, and selection using HIV-1(C) was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1(C(P51)), likely contributed to conferring a replication advantage on HIV-1(MIX(P51)) by reducing intravirion cyclophilin A content. HIV-1(MIX(P51)) apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1(MIX) through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1(MIX(P51)) should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.
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