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

被引:231
作者
Giffin, Michael J. [1 ]
Heaslet, Holly [2 ]
Brik, Ashraf [3 ]
Lin, Ying-Chuan [2 ]
Cauvi, Gabrielle [1 ]
Wong, Chi-Huey [3 ]
McRee, Duncan E. [4 ]
Elder, John H. [2 ]
Stout, C. David [2 ]
Torbett, Bruce E. [1 ]
机构
[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[4] Act Sight, San Diego, CA 92121 USA
关键词
D O I
10.1021/jm800149m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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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收藏
页码:6263 / 6270
页数:8
相关论文
共 46 条
[1]   A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro [J].
Amano, Masayuki ;
Koh, Yasuhiro ;
Das, Debananda ;
Li, Jianfeng ;
Leschenko, Sofiya ;
Wang, Yuan-Fang ;
Boross, Peter I. ;
Weber, Irene T. ;
Ghosh, Arun K. ;
Mitsuya, Hiroaki .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (06) :2143-2155
[2]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[3]   1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors [J].
Brik, A ;
Alexandratos, J ;
Lin, YC ;
Elder, JH ;
Olson, AJ ;
Wlodawer, A ;
Goodsell, DS ;
Wong, CH .
CHEMBIOCHEM, 2005, 6 (07) :1167-+
[4]   Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors [J].
Brik, A ;
Muldoon, J ;
Lin, YC ;
Elder, JH ;
Goodsell, DS ;
Olson, AJ ;
Fokin, VV ;
Sharpless, KB ;
Wong, CH .
CHEMBIOCHEM, 2003, 4 (11) :1246-1248
[5]   ASSESSMENT OF PHASE ACCURACY BY CROSS VALIDATION - THE FREE R-VALUE - METHODS AND APPLICATIONS [J].
BRUNGER, AT .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1993, 49 :24-36
[6]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[7]   Viral evolution in response to the broad-based retroviral protease inhibitor TL-3 [J].
Bühler, B ;
Lin, YC ;
Morris, G ;
Olson, AJ ;
Wong, CH ;
Richman, DD ;
Elder, JH ;
Torbett, BE .
JOURNAL OF VIROLOGY, 2001, 75 (19) :9502-9508
[8]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[9]   Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease [J].
Clemente, JC ;
Moose, RE ;
Hemrajani, R ;
Whitford, LRS ;
Govindasamy, L ;
Reutzel, R ;
McKenna, R ;
Agbandje-McKenna, M ;
Goodenow, MM ;
Dunn, BM .
BIOCHEMISTRY, 2004, 43 (38) :12141-12151
[10]   Remarks about protein structure precision [J].
Cruickshank, DWJ .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1999, 55 :583-601