COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

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SARS-CoV-2主蛋白酶的晶体学和亲电片段筛选

SARS-CoV-2引起的COVID-19缺乏有效的治疗方法。此外，尽管先前有人畜共患病暴发，但仍未针对紧密相关的冠状病毒，SARS-CoV-1或MERS-CoV开发抗病毒药物或疫苗。为了确定此类疗法的出发点，我们通过结合质谱和X射线方法对SARS-CoV-2主蛋白酶（这是两种必需的半胱氨酸病毒蛋白酶之一）进行了大规模的亲电试剂和非共价片段筛选病毒复制。我们的晶体学屏幕确定了跨越整个活动位点的71个匹配，以及二聚体界面的3个匹配。这些结构揭示了通过合并共价和非共价片段命中来快速开发更有效抑制剂的途径。一系列低反应性，改进了可处理的共价片段以发现改进的结合剂。这些组合命中提供了前所未有的结构和反应性信息，可用于正在进行的针对SARS-CoV-2主蛋白酶的基于结构的药物设计。