title: Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.
abstract: GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR(R8Q), PR(D30N), PR(I50V), PR(I54M), and PR(V82A) were analyzed in relation to kinetic data. The smaller valine side chain in PR(I50V) eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR(D30N) showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PR(R8Q) replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Shen
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.forename: Kalapala Venkateswara
authors.initials: KV
authors.lastname: Rao
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Xu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; C579815:GRL-0519; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1