The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model.

中文翻译：

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SARS-CoV-2 木瓜蛋白酶样蛋白酶 PLpro 的机制和抑制。

SARS-CoV-2 冠状病毒编码一个必需的木瓜蛋白酶样蛋白酶结构域，作为其非结构蛋白 (nsp)-3（即 SARS2 PLpro）的一部分，该结构域可切割病毒多蛋白，同时也去除泛素样 ISG15 蛋白修饰例如，Lys48 连接的多聚泛素活性较低。PLpro 与泛素和 ISG15 结合的结构表明，S1 泛素结合位点负责 ISG15 的高活性，而 S2 结合位点提供 Lys48 链特异性和切割效率。为了以重新利用的方法识别 PLpro 抑制剂，针对 SARS2 PLpro 筛选了 3,727 种独特的已批准药物和临床化合物，没有发现能够一致抑制 PLpro 或可以在反筛选中验证的化合物。更有希望的是，非共价小分子 SARS PLpro 抑制剂还针对 SARS2 PLpro，阻止细胞中 nsp3 的自我加工，并在 SARS-CoV-2 感染模型中显示出高效且优异的抗病毒活性。