1. Academic Validation
  2. Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses

  • ACS Infect Dis. 2022 Mar 11;8(3):596-611. doi: 10.1021/acsinfecdis.1c00631.
Brendan T Freitas 1 Daniil A Ahiadorme 2 Rahul S Bagul 1 Ian A Durie 1 Samir Ghosh 1 Jarvis Hill 2 Naomi E Kramer 3 Jackelyn Murray 4 Brady M O'Boyle 1 Emmanuel Onobun 2 Michael G Pirrone 1 Justin D Shepard 4 Suzanne Enos 1 Yagya P Subedi 1 Kapil Upadhyaya 1 Ralph A Tripp 4 Brian S Cummings 1 3 David Crich 1 2 Scott D Pegan 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 120 W. Green Street, Athens, Georgia 30602, United States.
  • 2 Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, Georgia 30602, United States.
  • 3 Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia 30602, United States.
  • 4 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, United States.
  • 5 Division of Biomedical Sciences, University of California Riverside, Riverside, California 92521, United States.
Abstract

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for Antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b Antiviral development of PLpro inhibitors.

Keywords

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

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