Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
J Med Chem. 2022 Feb 24;65(4):2848-2865. doi: 10.1021/acs.jmedchem.1c00509. Epub 2021 Apr 23.
The main protease (M) of SARS-CoV-2 is a validated antiviral drug target. Several M inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including , , , and , with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, () that is structurally distinct from the canonical M inhibitor . Significantly, is highly selective compared with covalent inhibitors such as , especially toward host proteases. The cocrystal structure of SARS-CoV-2 M with revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered , one of the most potent and selective noncovalent SARS-CoV-2 M inhibitors reported to date, and a novel binding pocket in M that can be explored for inhibitor design.
新型冠状病毒主蛋白酶（M）是一个经过验证的抗病毒药物靶点。已经有几种 M 抑制剂被报道具有很强的酶抑制和细胞抗病毒活性，包括 、 、 、 和 ，它们都含有一个反应性弹头，可使催化半胱氨酸 145 发生共价修饰。我们将基于结构的药物设计与一锅 Ugi 四组分反应相结合，发现了一种最有效的非共价抑制剂 （），它在结构上与典型的 M 抑制剂 不同。值得注意的是，与共价抑制剂如 相比， 具有很高的选择性，尤其是对宿主蛋白酶。与 SARS-CoV-2 M 形成的共晶结构揭示了一个以前未被探索的位于 S2 和 S4 口袋之间的结合位点。总的来说，这项研究发现了 ，这是迄今为止报道的最有效和选择性最高的非共价 SARS-CoV-2 M 抑制剂之一，也是 M 中一个可以探索抑制剂设计的新结合口袋。
