Vipirinin, a Coumarin-based HIV-1 Vpr Inhibitor, Interacts with a Hydrophobic Region of VPR
Vipirinin, a Coumarin-based HIV-1 Vpr Inhibitor, Interacts with a Hydrophobic Region of VPR
复制标题
DOI：
10.1074/jbc.m110.185397
复制
发表时间：
2011-04-22
影响因子：
4.8
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ong, Eugene Boon Beng;Watanabe, Nobumoto;Osada, Hiroyuki
人类免疫缺陷病毒1（HIV-1）病毒蛋白R（Vpr）是一种辅助蛋白，已被证明在HIV-1发病机制中具有多种作用。通过筛选RIKEN天然产物库中的化学库，我们鉴定了一种3-苯基香豆素基化合物，该化合物抑制酵母中Vpr的细胞周期阻滞活性和人类巨噬细胞的Vpr依赖性病毒感染。我们通过构效关系研究确定了其最小药效团，并产生了更有效的衍生物。我们检测到直接结合，并通过分析一组Vpr突变体，我们发现残基Glu-25和Gln-65的疏水区域可能参与抑制剂的结合。我们的研究结果揭示了Vpr上的靶向位点，并描绘了一种方便的方法来探索蛋白质上的其他靶向位点，使用小分子抑制剂作为生物探针。
The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) is an accessory protein that has been shown to have multiple roles in HIV-1 pathogenesis. By screening chemical libraries in the RIKEN Natural Products Depository, we identified a 3-phenyl coumarin-based compound that inhibited the cell cycle arrest activity of Vpr in yeast and Vpr-dependent viral infection of human macrophages. We determined its minimal pharmacophore through a structure-activity relationship study and produced more potent derivatives. We detected direct binding, and by assaying a panel of Vpr mutants, we found the hydrophobic region about residues Glu-25 and Gln-65 to be potentially involved in the binding of the inhibitor. Our findings exposed a targeting site on Vpr and delineated a convenient approach to explore other targeting sites on the protein using small molecule inhibitors as bioprobes.