title: A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant.
abstract: Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously described. We now show that compound 2, a copper(I)-catalyzed 1,2,3-triazole derived compound previously shown to be potently effective against wild-type protease (IC 50 = 6.0 nM), has low nM activity (IC 50 = 15.7 nM) against the multidrug-resistant 6X protease mutant. Compound 2 displays similar efficacy against wild-type and 6X HIV-1 in viral replication assays. While structural studies of compound 1 bound to wild type and mutant proteases revealed a progressive change in binding mode in the mutants, the 1.3 A resolution 6X protease-compound 2 crystal structure reveals nearly identical interactions for 2 as in the wild-type protease complex with very little change in compound 2 or protease conformation.
authors.affiliation: Department of Molecular Biology, and Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Giffin
authors.forename: Holly
authors.initials: H
authors.lastname: Heaslet
authors.forename: Ashraf
authors.initials: A
authors.lastname: Brik
authors.forename: Ying-Chuan
authors.initials: YC
authors.lastname: Lin
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Cauvi
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Duncan E
authors.initials: DE
authors.lastname: McRee
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.forename: C David
authors.initials: CD
authors.lastname: Stout
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
mesh_terms: D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry*; D002384:Catalysis; D002460:Cell Line; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000475:Alkenes; D001386:Azides; D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D014230:Triazoles; D003300:Copper; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1