Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-08-30 DOI:10.1016/j.bmcl.2024.129942

Wen Shen , Xinyao Chen , Liping Zhou , Yan Cheng , Yan Zhang , Xiangrui Jiang , Haiguo Sun , Jingshan Shen

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Abstract

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^pro), 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^pro. Meanwhile, novel 3CL^pro 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^pro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC₅₀ = 97 nM) and SARS-CoV-2 replicon (EC₅₀ = 45 nM) and low cytotoxicity (CC₅₀ > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL^pro inhibitors and provided the potent SARS-CoV-2 3CL^pro inhibitor (12b) which may be used for treating coronavirus infections.

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发现带丙烯酸酯弹头的 SARS-CoV-2 3CL 蛋白酶强效共价抑制剂。

COVID-19 自 2019 年 12 月爆发以来，在全球范围内对公共卫生和经济造成了严重后果。SARS-CoV-2 3C 样蛋白酶（3CLpro）对病毒复制至关重要，是开发抗病毒药物的诱人靶点。本研究利用多种迈克尔受体弹头来寻找针对 3CLpro 的强效共价抑制剂。同时，设计并合成了具有 P3-3,5-二氯-4-(2-(二甲基氨基)乙氧基)苯基的新型 3CLpro 抑制剂，这些抑制剂可与残基 Glu166 形成盐桥。其中，两个化合物 12b 和 12c 对 SARS-CoV-2 3CLpro 具有很高的抑制活性。进一步的研究表明，带有丙烯酸酯弹头的 12b 对 HCoV-OC43 （EC50 = 97 nM）和 SARS-CoV-2 复制子（EC50 = 45 nM）具有强效活性，对 Huh7 细胞的细胞毒性较低（CC50 > 10 μM）。总之，这项研究设计了两个系列的 3CLpro 抑制剂，并提供了有效的 SARS-CoV-2 3CLpro 抑制剂（12b），可用于治疗冠状病毒感染。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.