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

Nat Commun. 2025 Apr 3;16(1):2900. doi: 10.1038/s41467-025-57905-4.

Stefanie M Bader ^# ¹ ², Dale J Calleja ^# ¹ ², Shane M Devine ^# ³ ⁴, Nathan W Kuchel ^# ¹, Bernadine G C Lu ¹ ², Xinyu Wu ¹ ², Richard W Birkinshaw ¹ ², Reet Bhandari ¹ ², Katie Loi ¹ ², Rohan Volpe ¹ ², Yelena Khakham ¹, Amanda E Au ¹ ², Timothy R Blackmore ¹ ², Liana Mackiewicz ¹, Merle Dayton ¹, Jan Schaefer ¹ ², Lena Scherer ¹, Angus T Stock ¹ ², James P Cooney ¹ ², Kael Schoffer ¹ ², Ana Maluenda ¹, Elizabeth A Kleeman ¹ ⁵, Kathryn C Davidson ¹ ², Cody C Allison ¹ ², Gregor Ebert ¹ ², Gong Chen ⁶, Kasiram Katneni ⁶, Theresa A Klemm ¹ ², Ueli Nachbur ¹ ², Smitha Rose Georgy ⁷, Peter E Czabotar ¹ ², Anthony J Hannan ⁵ ⁸, Tracy L Putoczki ¹ ² ⁹, Maria Tanzer ¹ ², Marc Pellegrini ¹ ² ¹⁰, Bernhard C Lechtenberg ¹ ², Susan A Charman ⁶, Melissa J Call ¹ ², Jeffrey P Mitchell ¹ ², Kym N Lowes ¹ ², Guillaume Lessene ¹¹ ¹² ¹³, Marcel Doerflinger ¹⁴ ¹⁵, David Komander ¹⁶ ¹⁷

Affiliations

1 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
2 Department of Medical Biology, University of Melbourne, Melbourne, Australia.
3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. devine.s@wehi.edu.au.
4 Department of Medical Biology, University of Melbourne, Melbourne, Australia. devine.s@wehi.edu.au.
5 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
6 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
7 Anatomic Pathology - Veterinary Biosciences, Melbourne Veterinary School, University of Melbourne, Werribee, VIC, Australia.
8 Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia.
9 Department of Surgery, University of Melbourne, Melbourne, Australia.
10 Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, NSW, Australia.
11 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. glessene@wehi.edu.au.
12 Department of Medical Biology, University of Melbourne, Melbourne, Australia. glessene@wehi.edu.au.
13 Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Australia. glessene@wehi.edu.au.
14 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. doerflinger.m@wehi.edu.au.
15 Department of Medical Biology, University of Melbourne, Melbourne, Australia. doerflinger.m@wehi.edu.au.
16 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. dk@wehi.edu.au.
17 Department of Medical Biology, University of Melbourne, Melbourne, Australia. dk@wehi.edu.au.
# Contributed equally.

PMID: 40180914 DOI: 10.1038/s41467-025-57905-4

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-172350

WEHI-P8

PLpro Inhibitor

SARS-CoV

Infection

Name
Email *

	Sorry, but the email address you supplied was invalid.