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

Journal Article · · Nature Communications
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  1. Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  2. Univ. of Chicago, IL (United States)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health (NIH), National Inst. of Allergy and Infectious Diseases (NIAID); National Inst. of Health (NIH), National Institute of General Medical Sciences; U.S. Department of Health and Human Services; USDOE Office of Science (SC); Univ. of Chicago
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1768599
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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59 BASIC BIOLOGICAL SCIENCES
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