| Literature DB >> 33473130 |
Ziyang Fu1,2, Bin Huang1,2, Jinle Tang1,2, Shuyan Liu3, Ming Liu1,2, Yuxin Ye1,2, Zhihong Liu1,2, Yuxian Xiong1,2, Wenning Zhu1,2, Dan Cao1,2, Jihui Li1,2, Xiaogang Niu4, Huan Zhou5, Yong Juan Zhao1, Guoliang Zhang6, Hao Huang7,8.
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.Entities:
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Year: 2021 PMID： 33473130 PMCID： PMC7817691 DOI： 10.1038/s41467-020-20718-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919