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

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

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. One Sentence Summary Co-crystal structure of PLpro in complex with GRL0617 reveals the druggability of PLpro for SARS-CoV-2 treatment.