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• W2149088322 startingPage "2036" @default.
• W2149088322 abstract "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 [EC 50 ], 0.0005 to 0.0007 μM) with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ], 44.6 μM). GRL-0519 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by up to a 5 μM concentration of ritonavir, lopinavir, or atazanavir (EC 50 , 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-2 ROD . 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." @default.
• W2149088322 created "2016-06-24" @default.
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• W2149088322 date "2013-05-01" @default.
• W2149088322 modified "2023-10-10" @default.
• W2149088322 title "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 <i>In Vitro</i>" @default.
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• W2149088322 doi "https://doi.org/10.1128/aac.02189-12" @default.
• W2149088322 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3632947" @default.
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