期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 51, 期 20, 页码 6263-6270出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm800149m
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资金
- NIH [3 P30 AI036214-13S1, AI408820, GM48870, GM083658]
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 (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 angstrom resolution 6X protease-corn pound 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.
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