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

MBader S; Calleja, DJ; Devine, SM; Kuchel, NW; Lu, BGC; Wu, X; Birkinshaw, RW; Bhandari, R; Loi, K; Volpe, R; Khakham, Y; Au, AE; Blackmore, TR; Mackiewicz, L; Dayton, M; Schaefer, J; Scherer, L; Stock, AT; Cooney, JP; Schoffer, K; Maluenda, A; Kleeman, EA; Davidson, KC; Allison, CC; Ebert, G; Chen, G; Katneni, K; Klemm, TA; Nachbur, U; Georgy, SR; Czabotar, PE; Hannan, AJ; Putoczki, TL; Tanzer, M; Pellegrini, M; Lechtenberg, BC; Charman, SA; Call, MJ; Mitchell, JP; Lowes, KN; Lessene, G; Doerflinger, M; Komander, D

Author(s): MBader S; Calleja, DJ; Devine, SM; Kuchel, NW; Lu, BGC; Wu, X; Birkinshaw, RW; Bhandari, R; Loi, K; Volpe, R; Khakham, Y; Au, AE; Blackmore, TR; Mackiewicz, L; Dayton, M; Schaefer, J; Scherer, L; Stock, AT; Cooney, JP; Schoffer, K; Maluenda, A; Kleeman, EA; Davidson, KC; Allison, CC; Ebert, G; Chen, G; Katneni, K; Klemm, TA; Nachbur, U; Georgy, SR; Czabotar, PE; Hannan, AJ; Putoczki, TL; Tanzer, M; Pellegrini, M; Lechtenberg, BC; Charman, SA; Call, MJ; Mitchell, JP; Lowes, KN; Lessene, G; Doerflinger, M; Komander, D;
Details: Publication Year 2025-04-03,Volume 16,Issue #1,Page 2900
Journal Title: Nature Communications
Publication Type: Apr 3
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.
Publisher: Springer Nature
Keywords: Animals; *SARS-CoV-2/drug effects/enzymology; *Antiviral Agents/pharmacology/chemistry/therapeutic use; Mice; Disease Models, Animal; COVID-19/virology; Humans; *COVID-19 Drug Treatment; *Coronavirus 3C Proteases/antagonists & inhibitors/metabolism; Female; Post-Acute COVID-19 Syndrome
Research Division(s): Infection and Global Health; Structural Biology; Ubiquitin Signalling; New Medicines and Diagnostics; Advanced Technology and Biology; Blood Cells and Blood Cancer; Inflammation; Personalised Oncology
PubMed ID: 40180914
Publisher's Version: https://doi.org/10.1038/s41467-025-57905-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-57905-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-08 03:06:07

Last Modified: 2025-04-08 03:12:24