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

Fu, Z.; Huang, B.; Tang, J.; Liu, S.; Liu, M.; Ye, Y.; Liu, Z.; Xiong, Y.; Cao, D.; Li, J.; Niu, X.; Zhou, H.; Zhao, Y. J.; Zhang, G.; Huang, H.

doi:10.1101/2020.07.17.208959

bioRxiv · 10.1101/2020.07.17.208959

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

Fu, Z.·Huang, B.·Tang, J.·Liu, S.·Liu, M.·Ye, Y.·Liu, Z.·Xiong, Y.·Cao, D.·Li, J.·Niu, X.·Zhou, H.·Zhao, Y. J.·Zhang, G.·Huang, H.

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Abstract

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 M. 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 SummaryCo-crystal structure of PLpro in complex with GRL0617 reveals the druggability of PLpro for SARS-CoV-2 treatment.

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Fu, Z., Huang, B., Tang, J., Liu, S., Liu, M., Ye, Y., Liu, Z., Xiong, Y., Cao, D., Li, J., Niu, X., Zhou, H., Zhao, Y. J., Zhang, G., Huang, H.. 2020-07-18. Structural basis for the inhibition of the papain-like protease of SARS-CoV-2 by small molecules. https://doi.org/10.1101/2020.07.17.208959

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