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A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID

Author

Listed:
  • Stefanie M. Bader

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Dale J. Calleja

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Shane M. Devine

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Nathan W. Kuchel

    (Walter and Eliza Hall Institute of Medical Research)

  • Bernadine G. C. Lu

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Xinyu Wu

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Richard W. Birkinshaw

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Reet Bhandari

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Katie Loi

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Rohan Volpe

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Yelena Khakham

    (Walter and Eliza Hall Institute of Medical Research)

  • Amanda E. Au

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Timothy R. Blackmore

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Liana Mackiewicz

    (Walter and Eliza Hall Institute of Medical Research)

  • Merle Dayton

    (Walter and Eliza Hall Institute of Medical Research)

  • Jan Schaefer

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lena Scherer

    (Walter and Eliza Hall Institute of Medical Research)

  • Angus T. Stock

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • James P. Cooney

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kael Schoffer

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ana Maluenda

    (Walter and Eliza Hall Institute of Medical Research)

  • Elizabeth A. Kleeman

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kathryn C. Davidson

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Cody C. Allison

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gregor Ebert

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gong Chen

    (Monash University)

  • Kasiram Katneni

    (Monash University)

  • Theresa A. Klemm

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ueli Nachbur

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Smitha Rose Georgy

    (University of Melbourne)

  • Peter E. Czabotar

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Anthony J. Hannan

    (University of Melbourne
    University of Melbourne)

  • Tracy L. Putoczki

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    University of Melbourne)

  • Maria Tanzer

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marc Pellegrini

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Centenary Institute of Cancer Medicine and Cell Biology)

  • Bernhard C. Lechtenberg

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Susan A. Charman

    (Monash University)

  • Melissa J. Call

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jeffrey P. Mitchell

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kym N. Lowes

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Guillaume Lessene

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    University of Melbourne)

  • Marcel Doerflinger

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • David Komander

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The FDA-approved coronavirus antiviral Paxlovid targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of a COVID infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative antivirals that are addressing broader patient needs are urgently required. We here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses. Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients. Our lead compound offers protection against a range of PASC symptoms in this model, prevents lung pathology and reduces brain dysfunction. This provides proof-of-principle that PLpro inhibition may have clinical relevance for PASC prevention and treatment going forward.

Suggested Citation

  • Stefanie M. Bader & Dale J. Calleja & Shane M. Devine & Nathan W. Kuchel & Bernadine G. C. Lu & Xinyu Wu & Richard W. Birkinshaw & Reet Bhandari & Katie Loi & Rohan Volpe & Yelena Khakham & Amanda E. , 2025. "A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57905-4
    DOI: 10.1038/s41467-025-57905-4
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