School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China; Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
Bioorg Med Chem Lett. 2024 Nov 1;112:129942. doi: 10.1016/j.bmcl.2024.129942. Epub 2024 Aug 30.
COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CL. Meanwhile, novel 3CL inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CL. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC = 97 nM) and SARS-CoV-2 replicon (EC = 45 nM) and low cytotoxicity (CC > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL inhibitors and provided the potent SARS-CoV-2 3CL inhibitor (12b) which may be used for treating coronavirus infections.
自 2019 年 12 月爆发以来，COVID-19 在全球范围内对公共卫生和经济造成了严重后果。SARS-CoV-2 的 3C 样蛋白酶（3CL）对于病毒复制至关重要，是开发抗病毒药物的有吸引力的靶标。在这项研究中，利用几种迈克尔受体弹头来寻找针对 3CL 的有效共价抑制剂。同时，设计并合成了具有 P3-3,5-二氯-4-(2-(二甲氨基)乙氧基)苯基部分的新型 3CL 抑制剂，可能与残基 Glu166 形成盐桥。其中，两种化合物 12b 和 12c 对 SARS-CoV-2 3CL 表现出高抑制活性。进一步的研究表明，带有丙烯酰基弹头的 12b 对 HCoV-OC43（EC=97 nM）和 SARS-CoV-2 复制子（EC=45 nM）具有很强的活性，在 Huh7 细胞中细胞毒性低（CC>10 μM）。综上所述，本研究设计了两个系列的 3CL 抑制剂，并提供了有效的 SARS-CoV-2 3CL 抑制剂（12b），可用于治疗冠状病毒感染。
