Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: A new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains

被引:129
作者
Himmel, DM
Das, K
Clark, AD
Hughes, SH
Benjahad, A
Oumouch, S
Guillemont, J
Coupa, S
Poncelet, A
Csoka, I
Meyer, C
Andries, K
Nguyen, CH
Grierson, DS
Arnold, E [1 ]
机构
[1] Rutgers State Univ, CABM, Piscataway, NJ 08854 USA
[2] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA
[3] NCI, HIV Drug Resistance Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[4] Ctr Univ Orsay, Lab Pharmacochim, Sect Rech, UMR 176,CNRS,Inst Curie, F-91405 Orsay, France
[5] Johnson & Johnson Pharmaceut Res & Dev, Dept Med Chem, Val De Reuil, France
[6] Johnson & Johnson Pharmaceut Res & Dev, Virol Drug Discovery, B-2340 Beerse, Belgium
关键词
D O I
10.1021/jm0500323
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 angstrom resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.
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页码:7582 / 7591
页数:10
相关论文
共 56 条
[1]  
Arnold E, 1996, Drug Des Discov, V13, P29
[2]   Halogen bonds in biological molecules [J].
Auffinger, P ;
Hays, FA ;
Westhof, E ;
Ho, PS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (48) :16789-16794
[3]   4-benzyl and 4-benzoyl-3-dimethylaminopyridin-2 (1H)-ones:: In vitro evaluation of new c-3-amino-substituted and c-5,6-alkyl-substituted analogues against clinically important HIV mutant strains [J].
Benjahad, A ;
Croisy, M ;
Monneret, C ;
Bisagni, E ;
Mabire, D ;
Coupa, S ;
Poncelet, A ;
Csoka, I ;
Guillemont, J ;
Meyer, C ;
Andries, K ;
Pauwels, R ;
de Béthune, MP ;
Himmel, DM ;
Das, K ;
Arnold, E ;
Nguyen, CH ;
Grierson, DS .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (06) :1948-1964
[4]   4-Benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents:: Optimization and in vitro evaluation against clinically important HIV mutant strains [J].
Benjahad, A ;
Courté, K ;
Guillemont, J ;
Mabire, D ;
Coupa, S ;
Poncelet, A ;
Csoka, I ;
Andries, K ;
Pauwels, R ;
de Béthune, MP ;
Monneret, C ;
Bisagni, E ;
Nguyen, CH ;
Grierson, DS .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (22) :5501-5514
[5]   3-Iodo-4-phenoxypyridinones (IOPY's), a new family of highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase [J].
Benjahad, A ;
Guillemont, J ;
Andries, K ;
Nguyen, CH ;
Grierson, DS .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (24) :4309-4312
[6]  
Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254
[7]  
Clark AD, 1995, METHOD ENZYMOL, V262, P171, DOI 10.1016/0076-6879(95)62017-6
[8]  
Coffin J. M., 1997, RETROVIRUSES
[9]   HIV POPULATION-DYNAMICS IN-VIVO - IMPLICATIONS FOR GENETIC-VARIATION, PATHOGENESIS, AND THERAPY [J].
COFFIN, JM .
SCIENCE, 1995, 267 (5197) :483-489
[10]   Crystallography and the design of anti-AIDS drugs: Conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors [J].
Das, K ;
Lewi, PJ ;
Hughes, SH ;
Arnold, E .
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 2005, 88 (02) :209-231