Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses—including SARS-CoV, MERS-CoV, and SARS-CoV-2—is the papain-li...

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Veröffentlicht in:	PLoS pathogens Jg. 18; H. 12; S. e1011065
Hauptverfasser:	van Vliet, Vera J. E., Huynh, Nhan, Palà, Judith, Patel, Ankoor, Singer, Alex, Slater, Cole, Chung, Jacky, van Huizen, Mariska, Teyra, Joan, Miersch, Shane, Luu, Gia-Khanh, Ye, Wei, Sharma, Nitin, Ganaie, Safder S., Russell, Raquel, Chen, Chao, Maynard, Mindy, Amarasinghe, Gaya K., Mark, Brian L., Kikkert, Marjolein, Sidhu, Sachdev S.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 01.12.2022 Public Library of Science (PLoS)
Schlagworte:	Antiviral agents Antiviral drugs Biology and life sciences Catalytic Domain Cell culture Cloning Coronaviruses COVID-19 COVID-19 vaccines Crystal structure Disease transmission Enzymes Genomes Health aspects Humans Immune response Innate immunity Medicine and health sciences Middle East respiratory syndrome Pandemics Papain Papain - chemistry Papain - metabolism Peptide Hydrolases - metabolism Phages Physiological aspects Polyproteins Protease Proteases Proteins Replicase Replication Research and analysis methods SARS-CoV-2 - metabolism Severe acute respiratory syndrome coronavirus 2 Substrates Therapeutic targets Ubiquitin Ubiquitin - metabolism Vaccines Viral diseases Virus Replication Virus research Viruses Netherlands
ISSN:	1553-7374, 1553-7366, 1553-7374
Online-Zugang:	Volltext
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Zusammenfassung:	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses—including SARS-CoV, MERS-CoV, and SARS-CoV-2—is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.
Bibliographie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1011065