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Repurposing Drugs and Synergistic Combinations as Potential Therapies for Inhibiting SARS-CoV-2 and Coronavirus Replication

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    Repurposing Drugs and Synergistic Combinations as Potential Therapies for Inhibiting SARS-CoV-2 and Coronavirus Replication
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    • Richard Boulon*
      Richard Boulon
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
      *Email: [email protected]
      More by Richard Boulon
      Orcidhttps://orcid.org/0000-0002-6217-1222
    • Clément Mazeaud
      Clément Mazeaud
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Majid D. Farahani
      Majid D. Farahani
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Mathilde Broquière
      Mathilde Broquière
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Mustapha Iddir
      Mustapha Iddir
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Tania Charpentier
      Tania Charpentier
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Anaïs Anton
      Anaïs Anton
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
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    • Yann Ayotte
      Yann Ayotte
      NMX Research and Solutions|Accelerating drug discovery, 500 boulevard Cartier Ouest, Laval, Quebec H7V 5B7, Canada
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    • Simon Woo
      Simon Woo
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
      NMX Research and Solutions|Accelerating drug discovery, 500 boulevard Cartier Ouest, Laval, Quebec H7V 5B7, Canada
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    • Alain Lamarre*
      Alain Lamarre
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
      *Email: [email protected]
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    • Laurent Chatel-Chaix
      Laurent Chatel-Chaix
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
      More by Laurent Chatel-Chaix
    • Steven R. LaPlante*
      Steven R. LaPlante
      Institut National de la Recherche Scientifique−Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
      *Email: [email protected]
      More by Steven R. LaPlante
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2024, 7, 12, 4043–4055
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    https://doi.org/10.1021/acsptsci.4c00512
    Published November 5, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Drug repurposing can serve an important role in rapidly discovering medicament options for emerging microbial pandemics. In this study, a pragmatic approach is demonstrated for screening and testing drug combinations as potential broad-spectrum therapies against SARS-CoV-2 and other betacoronaviruses. Rapid cell-based phenotypic small molecule screens were executed using related common-cold-causing HCoV-OC43 betacoronavirus to identify replication inhibitors from a library of drugs approved by regulatory agencies for other indications. Given the best inhibitors, an expedient checkerboard strategy then served to identify synergistic drug combinations. These combinations were then validated using more challenging assays involving SARS-CoV-2 and variants. Promising drug combinations against multiple viral variants were discovered and involved Tilorone with Nelfinavir or Molnupiravir.

    Copyright © 2024 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.4c00512.

    • Methodology for Identifying Antagonistic (Chloroquine and Remdesivir) or Synergistic (Nitazoxanide and Remdesivir) Drug Combinations. Additional materials and methods used in drug combination studies, focusing on library curation and the method for applying synergy models such as BLISS, Loewe, and ZIP. A figure illustrates promising drugs’ efficacy and toxicity profiles of promising drugs against SARS-CoV-2, as measured in Huh7.5 and Calu3 cell lines. Results from fast-screening synergy tests in HCoV-OC43 are also presented. Finally, the study explores synergy in HCoV-OC43 and assesses the efficacy of drug combinations in SARS-CoV-2 synergy studies (PDF)

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    This article is cited by 1 publications.

    1. Christian Setz, Pia Rauch, Melanie Setz, Stephan Breitenberger, Stephan Plattner, Ulrich Schubert. Synergistic Antiviral Activity of European Black Elderberry Fruit Extract and Quinine Against SARS-CoV-2 and Influenza A Virus. Nutrients 2025, 17 (7) , 1205. https://doi.org/10.3390/nu17071205
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2024, 7, 12, 4043–4055
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsptsci.4c00512
    Published November 5, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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