1. Academic Validation
  2. Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease

Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease

  • ACS Infect Dis. 2020 Aug 14;6(8):2099-2109. doi: 10.1021/acsinfecdis.0c00168.
Brendan T Freitas 1 Ian A Durie 1 Jackelyn Murray 2 Jaron E Longo 1 Holden C Miller 1 David Crich 1 3 Robert Jeff Hogan 2 Ralph A Tripp 2 Scott D Pegan 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.
  • 2 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, United States.
  • 3 Department of Chemistry, Franklin College, University of Georgia, Athens, Georgia 30602, United States.
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, is a novel human betacoronavirus that is rapidly spreading worldwide. The outbreak currently includes over 3.7 million cases and 260,000 fatalities. As a betacoronavirus, SARS-CoV-2 encodes for a papain-like Protease (PLpro) that is likely responsible for cleavage of the coronavirus (CoV) viral polypeptide. The PLpro is also responsible for suppression of host innate immune responses by virtue of its ability to reverse host ubiquitination and ISGylation events. Here, the biochemical activity of SARS-CoV-2 Plpro against ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15) substrates is evaluated, revealing that the Protease has a marked reduction in its ability to process K48 linked Ub substrates compared to its counterpart in SARS-CoV. Additionally, its substrate activity more closely mirrors that of the PLpro from the Middle East respiratory syndrome coronavirus and prefers ISG15s from certain species including humans. Additionally, naphthalene based PLpro inhibitors are shown to be effective at halting SARS-CoV-2 Plpro activity as well as SARS-CoV-2 replication.

Keywords

COVID-19; ISG5; PLpro; coronavirus; severe acute respiratory syndrome 2; ubiquitin.

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