A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant

Michael J. Giffin, Holly Heaslet, Ashraf Brik, Ying Chuan Lin, Gabrielle Cauvi, Chi Huey Wong, Duncan E. McRee, John H. Elder, C. David Stout, Bruce E. Torbett

Research output: Contribution to journalArticlepeer-review

246 Scopus citations

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 C2-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 (IC50 = 6.0 nM), has low nM activity (IC50 = 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.

Original languageEnglish
Pages (from-to)6263-6270
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
DOIs
StatePublished - 23 Oct 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant'. Together they form a unique fingerprint.

Cite this