Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening
Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening
复制标题
DOI：
10.1016/s0166-3542(01)00222-4
复制
发表时间：
2002-06-01
影响因子：
7.6
通讯作者：
Garvey, EP
中科院分区：
文献类型：
--
作者：
Chapman, RL;Stanley, TB;Garvey, EP
用生物素化的人类免疫缺陷病毒(HIV)REV蛋白和氚REV反应元件RNA进行高通量闪烁邻近分析，筛选了超过50万个小分子。确定了几种化学类别的抑制剂和两种化学类别的结合促进剂，其相对分子质量范围为400-600。缓蚀剂最常见的结构基序是线性芳香族体系末端的酸性部分。大多数这些调节剂的EC50值在1-10微米的效力范围内，有些低于1微米。有几类化合物显示了结构-活性关系，表明小分子和大分子之间存在特定的分子相互作用。凝胶位移分析和表面等离子体共振分析证实了几个分子为抑制剂。此外，有一种抑制剂与REV蛋白结合，结合常数等于其IC50值，与结合REV的抑制机制一致。因此，小分子在体外可以调节这种大分子蛋白质-RNA相互作用。然而，在相关的基于细胞的检测中，没有化合物显示出HIV抗病毒活性。(C)2002 Elsevier Science B.V.保留所有权利。
A high throughput scintillation proximity assay with biotinylated human immunodeficiency virus (HIV) Rev protein and tritiated Rev response element RNA was used to screen over 500 000 small molecules. Several chemical classes of inhibitors and two chemical classes of enhancers of binding were identified, with the molecular weight range being 400-600. The most common structural motif of inhibitor was an acidic moiety at the end of a linear aromatic system. Most of these modulators had EC50 values in the 1 - 10 muM potency range, with several below 1 muM. Several classes displayed structure-activity relationships suggesting specific molecular interactions between small molecule and macromolecule. Several molecules were confirmed as inhibitors in a gel shift assay and by surface plasmon resonance analysis. Furthermore, one inhibitor was shown to bind the Rev protein with a binding constant equal to its IC50 value, consistent with the mechanism of inhibition being binding Rev. Thus, small molecules can modulate this macromolecular protein-RNA interaction in vitro. However, no compound demonstrated HIV antiviral activity in a relevant cell-based assay. (C) 2002 Elsevier Science B.V. All rights reserved.