A novel mechanism for inhibition of HIV-1 reverse transcriptase

被引:35
作者
Skillman, AG
Maurer, KW
Roe, DC
Stauber, MJ
Eargle, D
Ewing, TJA
Muscate, A
Davioud-Charvet, E
Medaglia, MV
Fisher, RJ
Arnold, E
Gao, HQ
Buckheit, R
Boyer, PL
Hughes, SH
Kuntz, ID
Kenyon, GL
机构
[1] Univ Michigan, Coll Pharm, Ann Arbor, MI 48109 USA
[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
[3] NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA
[4] Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA
[5] So Res Inst, Dept Infect Dis Res, Frederick, MD 21701 USA
关键词
D O I
10.1016/S0045-2068(02)00502-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The human immunodeficiency virus (HIV) epidemic is an important medical problem. Although combination drug regimens have produced dramatic decreases in viral load, current therapies do not provide a cure for HIV infection. We have used structure-based design and combinatorial medicinal chemistry to identify potent and selective HIV-1 reverse transcriptase (RT) inhibitors that may work by a mechanism distinct from that of current HIV drugs. The most potent of these compounds (compound 4, 2-naphthalenesulfonic acid, 4-hydroxy-7-[[[[5-hydroxy-6-[(4-cinnamylphenyl)-azo]-7-sulfo-2-naphthalenyl]amino]carbonyl]amino]-3-[(4-cinnamylphenyl)- azo], disodium salt) has an IC50 of 90 nM for inhibition of polymerase chain extension, a K-d of 40 nM for inhibition of DNA-RT binding, and an IC50 of 25-100 nM for inhibition of RNaseH cleavage. The parent compound (1) was as effective against 10 nucleoside and non-nucleoside resistant HIV-1 RT mutants as it was against the wild-type enzyme. Compound 4 inhibited HIV-1 RT and murine leukemia virus (MLV) RT, but it did not inhibit T-4 DNA polymerase, T-7 DNA polymerase, or the Klenow fragment at concentrations up to 200 nM. Finally, compound 4 protected cells from HIV-1 infection at a concentration more than 40 times lower than the concentration at which it caused cellular toxicity. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:443 / 458
页数:16
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