Crystal structure of SARS-CoV-2 papain-like protease.
10.1016/j.apsb.2020.08.014
- Author:
Xiaopan GAO
1
;
Bo QIN
1
;
Pu CHEN
1
;
Kaixiang ZHU
1
;
Pengjiao HOU
1
;
Justyna Aleksandra WOJDYLA
2
;
Meitian WANG
2
;
Sheng CUI
1
Author Information
1. NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
2. The Swiss Light Source (SLS) at the Paul Scherrer Institut, Villigen 5232, Switzerland.
- Publication Type:Journal Article
- Keywords:
Antiviral drug;
Crystal structure;
Drug design;
PLpro;
Proteinase inhibitor;
SARS-CoV-2
- From:
Acta Pharmaceutica Sinica B
2021;11(1):237-245
- CountryChina
- Language:English
-
Abstract:
The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC
