The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^pro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^pro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

由 SARS-CoV-2 引起的冠状病毒病 (COVID-19) 正在给人类带来巨大痛苦。迄今为止，还没有有效的药物可以直接治疗该疾病。在寻找针对 COVID-19 的药物时，我们对两个针对 SARS-CoV-2 主要蛋白酶 (M ^pro ) 的再利用药物库进行了高通量 X 射线晶体筛选，这对病毒复制至关重要。与常用的低复杂性分子的 X 射线片段筛选实验相比，我们的筛选测试了已批准的药物和临床试验中的药物。从三维蛋白质结构中，我们鉴定了 37 种与 M ^pro结合的化合物。在随后的基于细胞的病毒减少测定中，一种肽模拟物和六种非肽化合物在无毒浓度下显示出抗病毒活性。我们确定了两个变构结合位点，代表针对 SARS-CoV-2 药物开发的有吸引力的靶标。