Hamy F, Gelus N, Zeller M, Lazdins J L, Bailly C, Klimkait T
Novartis Pharma Research, Basel, Switzerland.
Chem Biol. 2000 Sep;7(9):669-76. doi: 10.1016/s1074-5521(00)00012-0.
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.
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.
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.
病毒耐药性的快速发展对当前抗HIV药物研发项目构成了严重限制。反过来，这一障碍成为利用替代病毒靶点的新努力的基础。
通过针对Tat驱动的HIV基因调控过程，我们发现了一类新的化合物以及一个新的靶点。候选化合物一方面通过经典方式抑制Tat/TAR复合物形成，但不与核酸结合。
结构以及分子建模/动力学表明，芪衍生物CGA137053直接与Tat蛋白结合，而不与TAR RNA结合。作为一种全新的第二特性，该化合物还通过阻止最近描述的HIV共受体CXCR4上调来拮抗游离Tat蛋白的TAR非依赖性活性。通过芪CGA137053，我们鉴定出一种强效、具有双重作用且化学上可行的Tat拮抗剂。该化合物具有高靶点特异性和低细胞毒性，不限于HIV抑制的Tat/TAR轴，且对HIV感染的原代人细胞具有高活性。
