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The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery

Open access
Fu, Ziyang, Huang, Bin, Tang, Jinle, Liu, Shuyan, Liu, Ming, Ye, Yuxin, Liu, Zhihong, Xiong, Yuxian, Zhu, Wenning, Cao, Dan, Li, Jihui, Niu, Xiaogang, Zhou, Huan, Zhao, Yong Juan, Zhang, Guoliang, Huang, Hao·2021·Nature Communications

Abstract

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 IC 50 of 2.1 μM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLpro C111S 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.

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Metadata

Authors
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, Y. J., Zhang, G., & Huang, H.
Venue
Nature Communications
Published
2021-01-20
Volume
12
Issue
1
Pages
488-488
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3125094078
Cited by
322
References
62
FWCI
19.18
Type
journal article
Language
en
Open access
gold

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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, Y. J., Zhang, G., & Huang, H. (2021). The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery. Nature Communications. https://doi.org/10.1038/s41467-020-20718-8

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