The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Protein Cell. 2022 Sep 28;14(1):17-27. doi: 10.1093/procel/pwac016. eCollection 2023 Jan.
The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M) and papain like protease (PL), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M inhibitors and 205 PL inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M and PL, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M inhibitors and over 20% of PL inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
全球 COVID-19 冠状病毒大流行已感染超过 1.09 亿人，导致超过 200 万人死亡，目前仍然缺乏有效的治疗药物。在这里，我们针对严重急性呼吸系统综合征冠状病毒 2 基因组中的主要蛋白酶 (M) 和木瓜蛋白酶样蛋白酶 (PL) 筛选了大约 180 万个小分子，鉴定出了 1851M 抑制剂和 205 个 PL 抑制剂，最佳命中物的活性低至纳摩尔/升。在这些抑制剂中，有 8 个小分子对 M 和 PL 都表现出双重抑制作用，具有作为 COVID-19 治疗更好候选物的潜力。我们在抗病毒测定中测试了每种蛋白酶的最佳抑制剂，其中超过 40%的 M 抑制剂和超过 20%的 PL 抑制剂在低细胞毒性下表现出对病毒的高抑制活性。我们以 1.8 Å 的分辨率确定了 SARS-CoV-2 M 与强效抑制剂 4a 复合物的 X 射线晶体结构。结合对接测定，我们的结果为未来抗 SARS-CoV-2 药物开发的研究提供了全面的资源。
