Abstract：
Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CLpro embodying an N-substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3-S4 subsites and connected to an invariant Leu-Gln P2-P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CLpro were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.
摘要：
已知人畜共患冠状病毒在人类中产生严重感染,并且在世界范围内已成为显著发病率和死亡率的原因。SARS-CoV-2是致命病例的最大和最新贡献者，尽管MERS-CoV在人畜共患冠状病毒中病死率最高。这些感染对全球公共卫生构成高风险，需要努力迅速发现抗病毒药物。因此，我们在此描述了一系列新型的冠状病毒3CLpro抑制剂，其中包含N-取代的2-吡咯烷酮支架，设想利用与S3-S4亚位点的有利相互作用，并连接到不变的Leu-GlnP2-P1识别元件。几种抑制剂在酶和基于细胞的测定中显示出纳摩尔抗病毒活性，无明显的细胞毒性。确定了与3CLpro结合的抑制剂的高分辨率晶体结构，以探测和鉴定与结合相关的分子决定子，为抑制剂的结构指导优化提供信息，并确认抑制剂的作用机理。
