7E35

Crystal structure of the SARS-CoV-2 papain-like protease (PLPro) C112S mutant bound to compound S43

Replaces:  7D7T

Summary for 7E35

• Entry DOI: 10.2210/pdb7e35/pdb
• Related: 7D6H
• Descriptor: Non-structural protein 3, ZINC ION, N-[(3-acetamidophenyl)methyl]-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide (3 entities in total)
• Functional Keywords: protease, deubiquitinase, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 72300.80

Authors

Liu, J.,Wang, Y.,Xu, X.,Pan, L. (deposition date: 2021-02-08, release date: 2021-03-17, Last modification date: 2023-11-29)

Primary citation

Shan, H.,Liu, J.,Shen, J.,Dai, J.,Xu, G.,Lu, K.,Han, C.,Wang, Y.,Xu, X.,Tong, Y.,Xiang, H.,Ai, Z.,Zhuang, G.,Hu, J.,Zhang, Z.,Li, Y.,Pan, L.,Tan, L.
Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2.
Cell Chem Biol, 28:855-, 2021

PubMed Abstract: The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.

PubMed: 33979649
DOI: 10.1016/j.chembiol.2021.04.020

Experimental method

X-RAY DIFFRACTION (2.4 Å)