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Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.
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.
  • van Vliet VJE; Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, South Holland, The Netherlands.
  • Huynh N; The Roslin Institute, University of Edinburgh, Midlothian, Scotland, United Kingdom.
  • Palà J; The Anvil Institute, Kitchener, Ontario, Canada.
  • Patel A; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Singer A; The Anvil Institute, Kitchener, Ontario, Canada.
  • Slater C; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Chung J; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
  • van Huizen M; The Anvil Institute, Kitchener, Ontario, Canada.
  • Teyra J; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Miersch S; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Luu GK; The Anvil Institute, Kitchener, Ontario, Canada.
  • Ye W; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Sharma N; Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, South Holland, The Netherlands.
  • Ganaie SS; The Anvil Institute, Kitchener, Ontario, Canada.
  • Russell R; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Chen C; The Anvil Institute, Kitchener, Ontario, Canada.
  • Maynard M; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Amarasinghe GK; The Anvil Institute, Kitchener, Ontario, Canada.
  • Mark BL; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
  • Kikkert M; The Anvil Institute, Kitchener, Ontario, Canada.
  • Sidhu SS; School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
PLoS Pathog ; 18(12): e1011065, 2022 12.
Article in English | MEDLINE | ID: covidwho-2197183
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitin / COVID-19 Topics: Vaccines / Variants Limits: Humans Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1011065

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitin / COVID-19 Topics: Vaccines / Variants Limits: Humans Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1011065