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

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. Au, Timothy R. Blackmore, Liana Mackiewicz, Merle Dayton, Jan Schaefer, Lena Scherer, Angus T. Stock, James P. Cooney, Kael Schoffer, Ana Maluenda, Elizabeth A. Kleeman, Kathryn C. Davidson, Cody C. Allison, Gregor Ebert, Gong Chen, Kasiram Katneni, Theresa A. Klemm, Ueli Nachbur, Smitha Rose Georgy, Peter E. Czabotar, Anthony J. Hannan, Tracy L. Putoczki, Maria Tanzer, Marc Pellegrini, Bernhard C. Lechtenberg, Susan A. Charman, Melissa J. Call, Jeffrey P. Mitchell, Kym N. Lowes, Guillaume Lessene (), Marcel Doerflinger () and David Komander ()
Additional contact information
Stefanie M. Bader: Walter and Eliza Hall Institute of Medical Research
Dale J. Calleja: Walter and Eliza Hall Institute of Medical Research
Shane M. Devine: Walter and Eliza Hall Institute of Medical Research
Nathan W. Kuchel: Walter and Eliza Hall Institute of Medical Research
Bernadine G. C. Lu: Walter and Eliza Hall Institute of Medical Research
Xinyu Wu: Walter and Eliza Hall Institute of Medical Research
Richard W. Birkinshaw: Walter and Eliza Hall Institute of Medical Research
Reet Bhandari: Walter and Eliza Hall Institute of Medical Research
Katie Loi: Walter and Eliza Hall Institute of Medical Research
Rohan Volpe: Walter and Eliza Hall Institute of Medical Research
Yelena Khakham: Walter and Eliza Hall Institute of Medical Research
Amanda E. Au: Walter and Eliza Hall Institute of Medical Research
Timothy R. Blackmore: Walter and Eliza Hall Institute of Medical Research
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
Lena Scherer: Walter and Eliza Hall Institute of Medical Research
Angus T. Stock: Walter and Eliza Hall Institute of Medical Research
James P. Cooney: Walter and Eliza Hall Institute of Medical Research
Kael Schoffer: Walter and Eliza Hall Institute of Medical Research
Ana Maluenda: Walter and Eliza Hall Institute of Medical Research
Elizabeth A. Kleeman: Walter and Eliza Hall Institute of Medical Research
Kathryn C. Davidson: Walter and Eliza Hall Institute of Medical Research
Cody C. Allison: Walter and Eliza Hall Institute of Medical Research
Gregor Ebert: Walter and Eliza Hall Institute of Medical Research
Gong Chen: Monash University
Kasiram Katneni: Monash University
Theresa A. Klemm: Walter and Eliza Hall Institute of Medical Research
Ueli Nachbur: Walter and Eliza Hall Institute of Medical Research
Smitha Rose Georgy: University of Melbourne
Peter E. Czabotar: Walter and Eliza Hall Institute of Medical Research
Anthony J. Hannan: University of Melbourne
Tracy L. Putoczki: Walter and Eliza Hall Institute of Medical Research
Maria Tanzer: Walter and Eliza Hall Institute of Medical Research
Marc Pellegrini: Walter and Eliza Hall Institute of Medical Research
Bernhard C. Lechtenberg: Walter and Eliza Hall Institute of Medical Research
Susan A. Charman: Monash University
Melissa J. Call: Walter and Eliza Hall Institute of Medical Research
Jeffrey P. Mitchell: Walter and Eliza Hall Institute of Medical Research
Kym N. Lowes: Walter and Eliza Hall Institute of Medical Research
Guillaume Lessene: Walter and Eliza Hall Institute of Medical Research
Marcel Doerflinger: Walter and Eliza Hall Institute of Medical Research
David Komander: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57905-4

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