Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany.
Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, Germany.
J Med Chem. 2022 Jul 14;65(13):9376-9395. doi: 10.1021/acs.jmedchem.2c00636. Epub 2022 Jun 16.
The main protease (M, 3CL) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M inhibitors. Compounds and exhibited excellent SARS-CoV-2 M inhibition with / of 58,700 M s ( = 0.0141 μM) and 27,200 M s ( = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds , , , , , and displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of and with SARS-CoV-2 M was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.
新型 SARS-CoV-2 主蛋白酶（Mpro，3CL）小分子硫代酯抑制剂的设计、合成与构效关系研究
SARS-CoV-2 的主要蛋白酶（Mpro，3CL）因其在病毒复制和转录过程中的关键作用，成为冠状病毒药物研发的一个有吸引力的靶标。本研究报告了新型小分子硫代酯作为 SARS-CoV-2 Mpro 抑制剂的设计、合成和构效关系。化合物 和 对 SARS-CoV-2 Mpro 具有优异的抑制活性，其半数最大抑制浓度（IC50）分别为 58700 M s（=0.0141 μM）和 27200 M s（=0.0332 μM）。在 Calu-3 和 Vero76 细胞中，化合物 、 、 、 、 、 对病毒表现出纳摩尔级别的抗病毒活性，同时对宿主细胞没有毒性。成功地对 与 SARS-CoV-2 Mpro 进行了共结晶，X 射线结构显示出与蛋白酶催化性半胱氨酸残基 Cys145 的共价结合。这些强效的 SARS-CoV-2 Mpro 抑制剂还抑制了其他β冠状病毒，包括 SARS-CoV-1 和 MERS-CoV 的 Mpro，表明它们可能对治疗更广泛的冠状病毒感染具有潜在应用价值。
