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

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.

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Publication Details

Journal
Nature Communications
Published
2025-04-03
DOI
https://doi.org/10.1038/s41467-025-57905-4
Citations
27
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
50.72

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article

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

Amanda E. Au, Yelena Khakham, Rohan Volpe, T. Blackmore et al.
27 citations
Nature Communications
Mosquito-borne diseases and control
50.72
article

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

Amanda E. Au, Yelena Khakham, Rohan Volpe, T. Blackmore, Merle Dayton, Reet Bhandari, Jan Schaefer, Nathan W. Kuchel, Angus T. Stock, Dale J. Calleja, Marcel Doerflinger, Shane M. Devine, Kasiram Katneni, Cody C. Allison, Theresa Klemm, Bernadine G.C. Lu, Jeffrey P. Mitchell, Melissa Call, Kael L. Schoffer, Tracy L. Putoczki, Maria C. Tanzer, Anthony J. Hannan, Smitha R. Georgy, Marc Pellegrini, Richard W. Birkinshaw, Peter E. Czabotar, Gregor Ebert, Ueli Nachbur, Ana Maluenda, Susan A. Charman, Bernhard C. Lechtenberg, Kym N. Lowes, James P. Cooney, Liana Mackiewicz, Elizabeth A. Kleeman, Guillaume Lessène, David Komander, Stefanie M. Bader, Katie Loi, Gong� Chen, Xinyu Wu, Kathryn C. Davidson, L.R. Scherer
article en
27 citations

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.

Nature CommunicationsVol. 16(1)
The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Florey Institute of Neuroscience and Mental Health (AU), Centenary Institute (AU), AgriBio (AU), Monash University (AU)
Australian Nuclear Science and Technology Organisation, Wellcome Trust, Australian Government, Australian Cancer Research Foundation, Australian Synchrotron, State Government of Victoria, MTPConnect, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 0%
Mosquito-borne diseases and control
50.72
DOIOpen Access PDFOpenAlex
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