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

Ziyang Fu, Bin Huang, Jinle Tang, Shuyan Liu, Ming Liu, Yuxin Ye, Zhihong Liu, Yuxian Xiong, Wenning Zhu, Dan Cao, Jihui Li, Xiaogang Niu, Huan Zhou, Yong Juan Zhao, Guoliang Zhang () and Hao Huang ()
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Ziyang Fu: Peking University Shenzhen Graduate School
Bin Huang: Peking University Shenzhen Graduate School
Jinle Tang: Peking University Shenzhen Graduate School
Shuyan Liu: Southern University of Science and Technology
Ming Liu: Peking University Shenzhen Graduate School
Yuxin Ye: Peking University Shenzhen Graduate School
Zhihong Liu: Peking University Shenzhen Graduate School
Yuxian Xiong: Peking University Shenzhen Graduate School
Wenning Zhu: Peking University Shenzhen Graduate School
Dan Cao: Peking University Shenzhen Graduate School
Jihui Li: Peking University Shenzhen Graduate School
Xiaogang Niu: Peking University
Huan Zhou: Chinese Academy of Sciences
Yong Juan Zhao: Peking University Shenzhen Graduate School
Guoliang Zhang: Southern University of Science and Technology
Hao Huang: Peking University Shenzhen Graduate School

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-020-20718-8

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