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

Fu, Ziyang1,2; Huang, Bin1,2; Tang, Jinle1,2; Liu, Shuyan3; Liu, Ming1,2; Ye, Yuxin1,2; Liu, Zhihong1,2; Xiong, Yuxian1,2; Zhu, Wenning1,2; Cao, Dan1,2; Li, Jihui1,2; Niu, Xiaogang4; Zhou, Huan5; Zhao, Yong Juan1; Zhang, Guoliang3; Huang, Hao1,2

2021-01-20

10.1038/s41467-020-20718-8

Nature Communications   影响因子和分区

2041-1723

2041-1723

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 mu M 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. The SARS-CoV-2 papain-like protease (PLpro) is of interest as a drug target. Here, the authors identify GRL0617 as a PPI (protein-protein interaction) inhibitor of SARS-CoV-2 PLpro that inhibits its deISGylating activity and present the mechanism of action of the compound through the GRL0617-bound PLpro crystal structure and NMR studies.

SCI

英语

NI论文 ; ESI高被引

通讯

National Natural Science Foundation of China[21977009] ; Shenzhen Science and Technology Innovation Committee[JCYJ20170412150913708] ; Shenzhen Bay Laboratory Open Research Program["SZBL2019062801010","SZBL202002271003"] ; Guangdong Scientific and Technological Project[2020B1111340076] ; Natural Science Foundation of the Guangdong Province[2018A0303130091]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000613566500023

NATURE RESEARCH

2-s2.0-85099696427

Web of Science

1.Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, State Key Lab Chem Oncogen, Shenzhen 518055, Peoples R China
2.Peking Univ, Shenzhen Grad Sch, Lab Struct Biol & Drug Discovery, Shenzhen 518055, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Peoples R China
4.Peking Univ, Beijing Nucl Magnet Resonance Ctr, Coll Chem & Mol Engn, Beijing 100871, Peoples R China
5.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai, Peoples R China

Fu, Ziyang,Huang, Bin,Tang, Jinle,et al. The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery[J]. Nature Communications,2021,12(1).

Fu, Ziyang.,Huang, Bin.,Tang, Jinle.,Liu, Shuyan.,Liu, Ming.,...&Huang, Hao.(2021).The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.Nature Communications,12(1).

Fu, Ziyang,et al."The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery".Nature Communications 12.1(2021).