A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant.
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.
Giffin
Michael J
MJ
Department of Molecular Biology, and Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Heaslet
Holly
H
Brik
Ashraf
A
Lin
Ying-Chuan
YC
Cauvi
Gabrielle
G
Wong
Chi-Huey
CH
McRee
Duncan E
DE
Elder
John H
JH
Stout
C David
CD
Torbett
Bruce E
BE
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
D000475:Alkenes; D001386:Azides; D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D014230:Triazoles; D003300:Copper; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1