ArticleAntimicrobial agents and chemotherapy2013
GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
- Advancements in development of novel class of HIV protease inhibitors.Annals of medicine · 2026Review
- Recent Advances in Heterocyclic HIV Protease Inhibitors.International journal of molecular sciences · 2025Review
- An orally available P1'-5-fluorinated MPNAS nexus · 2025Article
- Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chemical communications (Cambridge, England) · 2022Review
- 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
- Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications.Antimicrobial agents and chemotherapy · 2019Article
- Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.Biochemical and biophysical research communications · 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
- Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.ACS omega · 2018Article
- Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors.Asian journal of organic chemistry · 2018Article
- GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro.Scientific reports · 2017Article
- Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition.PloS one · 2017Article
- A fission yeast cell-based system for multidrug resistant HIV-1 proteases.Cell & bioscience · 2017Article
- A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413.Antimicrobial agents and chemotherapy · 2016Article
- Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation.Journal of medicinal chemistry · 2016Article
- Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.Journal of medicinal chemistry · 2016Review
- Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies.Journal of medicinal chemistry · 2015Article
- Enantioselective Synthesis of Dioxatriquinane Structural Motifs for HIV-1 Protease Inhibitors Using a Cascade Radical Cyclization.Tetrahedron letters · 2015Article
- Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir.Scientific reports · 2015Article
- A novel tricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor, GRL-0739, effectively inhibits the replication of multidrug-resistant HIV-1 variants and has a desirable central nervous system penetration property in vitro.Antimicrobial agents and chemotherapy · 2015Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
We report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0005 to 0.0007 μM) with minimal cytotoxicity (50% cytotoxic concentration [CC50], 44.6 μM). GRL-0519 blocked the infectivity and replication of HIV-1NL4-3 variants selected by up to a 5 μM concentration of ritonavir, lopinavir, or atazanavir (EC50, 0.0028 to 0.0033 μM). GRL-0519 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2ROD. The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2' binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PI-resistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.
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