The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.
The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.
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DOI：
10.1038/s41467-020-20718-8
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发表时间：
2021-01-20
影响因子：
16.6
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Fu Z;Huang B;Tang J;Liu S;Liu M;Ye Y;Liu Z;Xiong Y;Zhu W;Cao D;Li J;Niu X;Zhou H;Zhao YJ;Zhang G;Huang H
SARS-CoV-2是导致COVID-19大流行的病原体。SARS-CoV-2木瓜蛋白酶样半胱氨酸蛋白酶（PLpro）在病毒成熟、宿主炎症失调和抗病毒免疫反应中发挥重要作用。PLpro的多种功能使其成为一个很有前景的药物靶点。因此，我们筛选了一个批准的药物库，并检查了可用的抗PLpro抑制剂。GRL0617的体外IC50为2.1 μM，在细胞实验中显示出有效的抗病毒抑制作用。SARS-CoV-2 PLproC111S与GRL0617复合物的共晶结构表明，GRL0617是一种非共价抑制剂，位于PLpro的泛素特异性蛋白酶（USP）结构域。核磁共振数据表明，GRL0617阻断了ISG15 c端与PLpro的结合。利用截断的ISG15突变体，我们发现ISG15的c端在结合PLpro中起主导作用。结构分析表明，PLpro中ISG15 c端结合口袋贡献了不成比例的结合能，因此该口袋是针对PLpro的抗病毒药物发现的热点。SARS-CoV-2木瓜蛋白酶（PLpro）作为一种药物靶点引起了人们的兴趣。本研究中，作者鉴定GRL0617为SARS-CoV-2 PLpro的PPI（蛋白-蛋白相互作用）抑制剂，可抑制其去isgyylation活性，并通过GRL0617结合的PLpro晶体结构和NMR研究展示了该化合物的作用机制。
SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 μM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro. The SARS-CoV-2 papain-like protease (PLpro) is of interest as a drug target. Here, the authors identify GRL0617 as a PPI (protein–protein interaction) inhibitor of SARS-CoV-2 PLpro that inhibits its deISGylating activity and present the mechanism of action of the compound through the GRL0617-bound PLpro crystal structure and NMR studies.
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影响因子：
16.8
作者：
Jin, Zhenming;Zhao, Yao;Rao, Zihe
通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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