Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Chiyoda-ku, Tokyo, 101-0062, Japan.
Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo, 162-8655, Japan.
Eur J Med Chem. 2024 Dec 15;280:116963. doi: 10.1016/j.ejmech.2024.116963. Epub 2024 Oct 18.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M) and a papain-like protease (PL), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL showed that GRL-0048 noncovalently interacts with PL, and there is a newly identified binding pocket in PL. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1, 2b, and 3h, that have more potent inhibitory activity than GRL-0048.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）可引起 2019 年冠状病毒病（COVID-19），目前尚未被消灭。SARS-CoV-2 有两种蛋白酶，一种主蛋白酶（M）和一种木瓜蛋白酶样蛋白酶（PL），它们共同加工两种翻译的非结构多蛋白 pp1a 和 pp1ab，以产生功能性病毒蛋白。在这项研究中，使用 GRL-0048 作为先导物设计并合成了针对 SARS-CoV-2 PL 的有效抑制剂。GRL-0048 与 SARS-CoV-2 PL 的对接模拟表明，GRL-0048 与 PL 非共价相互作用，并且在 PL 中有一个新确定的结合口袋。随后对 GRL-0048 进行了构效关系研究，开发出了几种抑制剂，特别是化合物 1、2b 和 3h，它们比 GRL-0048 具有更强的抑制活性。
