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Structural basis for the inhibition of the papain-like protease of SARS-CoV-2 by small molecules

By Ziyang Fu, Bin Huang, Jinle Tang, Shuyan Liu, Ming Liu, Yuxin Ye, Zhihong Liu, Yuxian Xiong, Dan Cao, Jihui Li, Xiaogang Niu, Huan Zhou, Yong Juan Zhao, Guoliang Zhang, Hao Huang

Posted 18 Jul 2020
bioRxiv DOI: 10.1101/2020.07.17.208959

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease has been implicated in virus maturation, dysregulation of host inflammation and antiviral immune responses. We showed that PLpro preferably cleaves the K48-ubiquitin linkage while also being capable of cleaving ISG15 modification. The multiple functions of PLpro render it a promising drug target. Therefore, we screened an FDA-approved drug library and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising IC50 of 2.1 μM. The co-crystal structure of SARS-CoV-2 PLpro-C111S in complex with GRL0617 suggests that GRL0617 is a non-covalent inhibitor. NMR data indicate that GRL0617 blocks the binding of ISG15 to PLpro. The antiviral activity of GRL0617 reveal that PLpro is a promising drug target for therapeutically treating COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

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