ArticleJournal of virology2012
Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1.
Article in Journal of virology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
21 citing papers in PubMed, 24 citations in OpenAlex.
- GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants.Science advances · 2023Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chemical communications (Cambridge, England) · 2022Review
- Article
- Precursors of Viral Proteases as Distinct Drug Targets.Viruses · 2021Review
- Design, Synthesis, and X-ray Studies of Potent HIV-1 Protease Inhibitors with P2-Carboxamide Functionalities.ACS medicinal chemistry letters · 2020Article
- Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.Journal of medicinal chemistry · 2020Article
- A novel HIV-1 protease inhibitor, GRL-044, has potent activity against various HIV-1s with an extremely high genetic barrier to the emergence of HIV-1 drug resistance.Global health & medicine · 2019Article
- Novel Protease Inhibitors Containing C-5-ModifiedAntimicrobial agents and chemotherapy · 2019Article
- Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.Journal of medicinal chemistry · 2018Article
- Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.Journal of medicinal chemistry · 2018Article
- GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants.Antimicrobial agents and chemotherapy · 2018Article
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- Early phase dynamics of traceable mCherry fluorescent protein-carrying HIV-1 infection in human peripheral blood mononuclear cells-transplanted NOD/SCID/Jak3Antiviral research · 2017Article
- HIV-1 Protease Dimerization Dynamics Reveals a Transient Druggable Binding Pocket at the Interface.Scientific reports · 2015Article
- C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir.Journal of virology · 2015Article
- Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Understanding HIV-1 protease autoprocessing for novel therapeutic development.Future medicinal chemistry · 2013Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Tipranavir (TPV), a protease inhibitor (PI) inhibiting the enzymatic activity and dimerization of HIV-1 protease, exerts potent activity against multi-PI-resistant HIV-1 isolates. When a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (HIV(11MIX)), which included HIV(B) and HIV(C), was selected against TPV, HIV(11MIX) rapidly (by 10 passages [HIV(11MIX)(P10)]) acquired high-level TPV resistance and replicated at high concentrations of TPV. HIV(11MIX)(P10) contained various amino acid substitutions, including I54V and V82T. The intermolecular FRET-based HIV-1 expression assay revealed that TPV's dimerization inhibition activity against cloned HIV(B) (cHIV(B)) was substantially compromised. The introduction of I54V/V82T into wild-type cHIV(NL4-3) (cHIV(NL4-3(I54V/V82T))) did not block TPV's dimerization inhibition or confer TPV resistance. However, the introduction of I54V/V82T into cHIV(B) (cHIV(B)(I54V/V82T)) compromised TPV's dimerization inhibition and cHIV(B)(I54V/V82T) proved to be significantly TPV resistant. L24M was responsible for TPV resistance with the cHIV(C) genetic background. The introduction of L24M into cHIV(NL4-3) (cHIV(NL4-3(L24M))) interfered with TPV's dimerization inhibition, while L24M increased HIV-1's susceptibility to TPV with the HIV(NL4-3) genetic background. When selected with TPV, cHIV(NL4-3(I54V/V82T)) most readily developed TPV resistance and acquired E34D, which compromised TPV's dimerization inhibition with the HIV(NL4-3) genetic background. The present data demonstrate that certain amino acid substitutions compromise TPV's dimerization inhibition and confer TPV resistance, although the loss of TPV's dimerization inhibition is not always associated with significantly increased TPV resistance. The findings that TPV's dimerization inhibition is compromised with one or two amino acid substitutions may explain at least in part why the genetic barrier of TPV against HIV-1's development of TPV resistance is relatively low compared to that of darunavir.
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Registered trials
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