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Article

A Copper(I)-Catalyzed 1,2,3-Triazole Azide−Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease Variant

Supporting Info

Michael J. Giffin^†, Holly Heaslet^‡^#, Ashraf Brik^§, Ying-Chuan Lin^‡, Gabrielle Cauvi^†, Chi-Huey Wong^§, Duncan E. McRee, John H. Elder^‡, C. David Stout^‡ and Bruce E. Torbett*^†

Departments of Molecular and Experimental Medicine, Molecular Biology, and Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, Active Sight, 4045 Sorrento Valley Boulevard, San Diego, California 92121

J. Med. Chem., 2008, 51 (20), pp 6263–6270

DOI: 10.1021/jm800149m

Publication Date (Web): September 30, 2008

†

Department of Molecular and Experimental Medicine, The Scripps Research Institute.

Equally contributing authors.

‡

Department of Molecular Biology, The Scripps Research Institute.

Current address: Pfizer Global Research & Development, 558 Eastern Point Road, Groton, CT 06340.

Department of Chemistry, The Scripps Research Institute.

Current address: Department of Chemistry, Ben-Gurion University, P.O. Box 653, Beer Sheva 84105, Israel.

Active Sight.

* To whom correspondence should be addressed. Phone: (858) 784-9123. Fax: (858) 784-7714. E-mail: betorbet@scripps.edu.

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 Å 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.