A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID
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.
Article Details
Authors (43)
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
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry
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
David Komander