Identification of FDA-approved bifonazole as a SARS-CoV-2 blocking agent following a bioreporter drug screen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Zaid Taha, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Rozanne Arulanandam, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Glib Maznyi, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Elena Godbout, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Madalina E Carter-Timofte
  • Naziia Kurmasheva
  • Line S Reinert
  • Andrew Chen, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Mathieu J F Crupi, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Stephen Boulton, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Geneviève Laroche, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Alexandra Phan, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Reza Rezaei, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Nouf Alluqmani, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Anna Jirovec, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Alexandra Acal, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Emily E F Brown, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Ragunath Singaravelu, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Julia Petryk, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Manja Idorn
  • Kyle G Potts, University of Calgary, Calgary, Canada.
  • ,
  • Hayley Todesco, University of Calgary, Calgary, Canada.
  • ,
  • Cini John, University of Calgary, Calgary, Canada.
  • ,
  • Douglas J Mahoney, University of Calgary, Calgary, Canada.
  • ,
  • Carolina S Ilkow, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Patrick Giguère, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Tommy Alain, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Marceline Côté, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Søren R Paludan
  • David Olagnier
  • John C Bell, University of Ottawa Heart Institute, University of Ottawa, Ottawa
  • ,
  • Taha Azad, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • ,
  • Jean-Simon Diallo, University of Ottawa Heart Institute, University of Ottawa, Ottawa

We established a split nanoluciferase complementation assay to rapidly screen for inhibitors that interfere with binding of the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein with its target receptor, angiotensin-converting enzyme 2 (ACE2). After a screen of 1,200 US Food and Drug Administration (FDA)-approved compounds, we identified bifonazole, an imidazole-based antifungal agent, as a competitive inhibitor of RBD-ACE2 binding. Mechanistically, bifonazole binds ACE2 around residue K353, which prevents association with the RBD, affecting entry and replication of spike-pseudotyped viruses as well as native SARS-CoV-2 and its variants of concern (VOCs). Intranasal administration of bifonazole reduces lethality in K18-hACE2 mice challenged with vesicular stomatitis virus (VSV)-spike by 40%, with a similar benefit after live SARS-CoV-2 challenge. Our screen identified an antiviral agent that is effective against SARS-CoV-2 and VOCs such as Omicron that employ the same receptor to infect cells and therefore has high potential to be repurposed to control, treat, or prevent coronavirus disease 2019 (COVID-19).

OriginalsprogEngelsk
TidsskriftMolecular Therapy
ISSN1525-0016
DOI
StatusE-pub ahead of print - 6 maj 2022

Bibliografisk note

Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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