CITSAM, Fundación Universidad Católica de Valencia San Vicente Mártir, C/Quevedo 2 46001, Valencia, Spain; Escuela de Doctorado, Fundación Universidad Católica de Valencia San Vicente Mártir, Spain.
Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo km 2 28220, Majadahonda, Spain; CIBERINFEC, Instituto de Salud Carlos III, Spain.
Biochem Pharmacol. 2023 Sep;215:115734. doi: 10.1016/j.bcp.2023.115734. Epub 2023 Aug 6.
The complex between the Rev protein of HIV-1 and the Rev Recognition Element (RRE) within the virus RNA promotes nuclear export of unspliced or incompletely spliced viral transcripts and is required for virus transmission. Here, we have screened a virtual collection of compounds using a pharmacophore based on the chemical similarity of previously characterized inhibitors to identify new chemical scaffolds blocking the RRE-Rev interaction. The best molecules discovered with this strategy inhibited the complex by binding to the RRE and exhibited substantial antiretroviral activity (between 0.582 and 11.3 μM EC values) likely associated to inhibitory actions on viral transcription and Rev function. These results have allowed us to identify structural features required for RRE-Rev inhibition as well as to add new compounds to the pool of possible candidates for developing antiretroviral agents based on blockage of HIV-1 RNA biogenesis.
HIV-1 的 Rev 蛋白与病毒 RNA 中的 Rev 识别元件（RRE）形成复合物，促进未剪接或不完全剪接的病毒转录本的核输出，这对于病毒传播是必需的。在这里，我们使用基于先前表征的抑制剂的化学相似性的药效团对虚拟化合物库进行了筛选，以鉴定新的化学支架来阻断 RRE-Rev 相互作用。该策略发现的最佳分子通过与 RRE 结合来抑制复合物，表现出显著的抗逆转录病毒活性（EC 值在 0.582 到 11.3 μM 之间），可能与对病毒转录和 Rev 功能的抑制作用有关。这些结果使我们能够确定抑制 RRE-Rev 所需的结构特征，并为基于阻断 HIV-1 RNA 生物发生的抗逆转录病毒药物的开发增加新的候选化合物。
