The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PL^pro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PL^pro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

由 SARS-CoV-2 引起的 COVID-19 大流行在社会和经济上都是毁灭性的。尽管进行了前所未有的研究工作和可用的疫苗，但仍然缺乏有效的治疗方法来限制严重的疾病和死亡率。使用高通量筛选，我们将吖啶黄 (ACF) 鉴定为有效的木瓜蛋白酶样蛋白酶 (PL ^pro ) 抑制剂。NMR 滴定和共晶结构证实吖啶黄以意想不到的结合模式阻断 PL ^{pro催化口袋。}我们表明，该药物在细胞模型、小鼠体内和离体中以纳摩尔浓度抑制病毒复制在人类气道上皮细胞中，对 SARS-CoV-2 和其他β冠状病毒具有广泛的活性。考虑到吖啶黄是一些国家批准的廉价药物，它可能会立即在临床试验中进行测试，并在当前的大流行和未来的爆发中发挥重要作用。