The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CL^pro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CL^pro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CL^pro and MERS-CoV 3CL^pro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.

中文翻译：

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严重急性呼吸综合征冠状病毒2 3C样蛋白酶的有效螺环抑制剂的结构引导设计

持续的 COVID-19 大流行对公共卫生造成的全球影响使得发现和开发针对病毒和/或宿主目标的直接作用抗病毒药物势在必行。SARS-CoV-2 3C 样蛋白酶 (3CL ^pro ) 已成为发现 SARS-CoV-2 疗法的有效靶点，因为它在病毒复制中发挥着关键作用。^{我们在此描述了 SARS-CoV-2 3CL pro}高效抑制剂的结构引导设计，该抑制剂在其结构中融入了新颖的螺环设计元素，旨在通过进入新的化学空间来优化效力。已鉴定出具有 nM 效力和高安全指数的SARS-CoV-2 3CL ^pro和 MERS-CoV 3CL ^{pro抑制剂。}使用高分辨率共晶结构建立了抑制剂的作用机制和与结合相关的结构决定因素。