Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2.
Cell Chem Biol
; 28(6): 855-865.e9, 2021 06 17.
Article
in English
| MEDLINE | ID: covidwho-1201399
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 IC50. 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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protease Inhibitors
/
Drug Delivery Systems
/
Drug Development
/
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Animals
/
Humans
Language:
English
Journal:
Cell Chem Biol
Year:
2021
Document Type:
Article
Affiliation country:
J.chembiol.2021.04.020
Similar
MEDLINE
...
LILACS
LIS