Back to Search Start Over

Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design.

Authors :
Rut W
Lv Z
Zmudzinski M
Patchett S
Nayak D
Snipas SJ
El Oualid F
Huang TT
Bekes M
Drag M
Olsen SK
Source :
Science advances [Sci Adv] 2020 Oct 16; Vol. 6 (42). Date of Electronic Publication: 2020 Oct 16 (Print Publication: 2020).
Publication Year :
2020

Abstract

Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Details

Language :
English
ISSN :
2375-2548
Volume :
6
Issue :
42
Database :
MEDLINE
Journal :
Science advances
Publication Type :
Academic Journal
Accession number :
33067239
Full Text :
https://doi.org/10.1126/sciadv.abd4596