Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors

Jerzy Osipiuk, Saara-Anne Azizi, Steve Dvorkin, Michael Endres, Robert Jedrzejczak, Krysten A. Jones, Soowon Kang, Rahul S. Kathayat, Youngchang Kim, Vladislav G. Lisnyak, Samantha L. Maki, Vlad Nicolaescu, Cooper A. Taylor, Christine Tesar, Yu-An Zhang, Zhiyao Zhou, Glenn Randall, Karolina Michalska, Scott A. Snyder (), Bryan C. Dickinson () and Andrzej Joachimiak ()
Additional contact information
Jerzy Osipiuk: University of Chicago
Saara-Anne Azizi: University of Chicago
Steve Dvorkin: University of Chicago
Michael Endres: University of Chicago
Robert Jedrzejczak: University of Chicago
Krysten A. Jones: University of Chicago
Soowon Kang: University of Chicago
Rahul S. Kathayat: University of Chicago
Youngchang Kim: University of Chicago
Vladislav G. Lisnyak: University of Chicago
Samantha L. Maki: University of Chicago
Vlad Nicolaescu: University of Chicago
Cooper A. Taylor: University of Chicago
Christine Tesar: University of Chicago
Yu-An Zhang: University of Chicago
Zhiyao Zhou: University of Chicago
Glenn Randall: University of Chicago
Karolina Michalska: University of Chicago
Scott A. Snyder: University of Chicago
Bryan C. Dickinson: University of Chicago
Andrzej Joachimiak: University of Chicago

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses. We report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme. We determined the high resolution structure of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors. This collection of structures details inhibitors recognition and interactions providing fundamental molecular and mechanistic insight into PLpro. All compounds inhibit the peptidase activity of PLpro in vitro, some block SARS-CoV-2 replication in cell culture assays. These findings will accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21060-3

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DOI: 10.1038/s41467-021-21060-3

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