Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
Int J Mol Sci. 2023 Jan 7;24(2):1215. doi: 10.3390/ijms24021215.
This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, was demonstrated with lower cytotoxicity (CC = 125 µM). In the reverse transcriptase inhibitory assay, exhibited an IC value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.
本研究证明了设计一种新型 HIV-1 共价抑制剂的概念验证，该抑制剂针对 HIV-1 非核苷类逆转录酶抑制剂结合口袋中高度保守的 Tyr318，以改善耐药谱。该靶抑制剂在结构中带有氟硫酸酯弹头，被发现是一种有效的抑制剂（EC=11-246 nM），对 HIV-1 IIIB 和一组 NNRTIs 耐药株具有很强的抑制作用，远远优于 NVP 和 EFV。此外，它的细胞毒性（CC=125 µM）更低。在逆转录酶抑制试验中，用 ELISA 法测定化合物 对 HIV-1 的 IC 值为 0.057 µM，MALDI-TOF MS 数据表明化合物与酶形成共价结合模式。此外，分子模拟也表明，化合物可以与 Tyr318 形成共价结合。
