title: Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease.
abstract: The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A, and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PR(D30N), PR(I50V), PR(V82A), and PR(I84V) relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR(D30N), where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11-1.60 Angstrom) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PR(D30N) and PR(V82A) showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PR(I50V) and PR(I84V). Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.
authors: Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, USA.
authors: Yuan-Fang
authors: YF
authors: Wang
authors: Yunfeng
authors: Y
authors: Tie
authors: Peter I
authors: PI
authors: Boross
authors: Jozsef
authors: J
authors: Tozser
authors: Arun K
authors: AK
authors: Ghosh
authors: Robert W
authors: RW
authors: Harrison
authors: Irene T
authors: IT
authors: Weber
mesh_terms: D018360:Crystallography, X-Ray; D000069454:Darunavir; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: C522027:(2,8-dioxabicyclo(3.3.0)oct-6-yl)-N-(4-((3,4-methylenedioxyphenyl)sulfonyl-(2-methylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl) carbamate; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; D000069454:Darunavir
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