Blocking HIV replication by targeting Tat protein

被引:31
作者
Hamy, F
Gelus, N
Zeller, M
Lazdins, JL
Bailly, C
Klimkait, T [1 ]
机构
[1] Univ Basel, Inst Med Microbiol, CH-4003 Basel, Switzerland
[2] Novartis Pharma Res, CH-4002 Basel, Switzerland
[3] INSERM Unite 524, F-59045 Lille, France
[4] Solvias AG, CH-4002 Basel, Switzerland
来源
CHEMISTRY & BIOLOGY | 2000年 / 7卷 / 09期
关键词
CXCR4; coreceptor; HIV infection; Tat inhibition;
D O I
10.1016/S1074-5521(00)00012-0
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
Background: A rapid development of viral drug resistance poses a serious limitation in the current drug development programs against HIV. In turn, this obstacle forms the basis for new efforts. which utilize alternative viral targets. Results: By aiming at the Tat-driven process of HIV gene regulation, we discovered a new class of compounds as well as a novel target. The candidate compound acts on the one hand by classically inhibiting Tat/TAR complexation, however, without binding to nucleic acids. Conclusions: Structure and molecular modeling/dynamics suggest that the stilbene derivative CGA137053 directly binds to Tat protein but not TAR RNA. As a completely new, second property, the compound also antagonizes a TAR-independent activity of free Tat protein by preventing the recently described upregulation of the HIV coreceptor CXCR4. With the stilbene CGA137053, we have identified a potent, double-hitting and chemically feasible Tat antagonist. The compound possesses high target specificity and low cytotoxicity, is not restricted to the Tat/TAR axis of HIV inhibition and highly active on HIV-infected, primary human cells.
引用
收藏
页码:669 / 676
页数:8
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