Poster Presentation Inaugural Australian Ubiquitin Summit 2025

Antivirals Targeting Papain-Like Protease (PLpro) (#123)

Shane Devine 1 , Stefanie Bader 1 , Dale Calleja 1 , Nathan Kuchel 1 , Marcel Doerflinger 1 , Guillaume Lessene 1 , David Komander 1
  1. WEHI, Parkville, VIC, Australia

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, Paxlovid1, targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of an 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. Therefore, alternative antivirals against novel protein targets that address broader patient needs are urgently required.

Here we report our drug discovery efforts to target papain-like protease (PLpro), a further essential coronaviral protease2, 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 model3 of severe acute disease.

Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients, including lung, heart, gut and brain dysfunction. Our lead compound offers protection against PASC in this model, prevents lung pathology and reduces brain dysfunction, providing a potential treatment option for PASC sufferers going forward.

This presentation will outline the drug discovery campaign of our PLpro inhibitors from high throughput screen to orally active lead compound in a SARS-CoV-2 mouse infection model4.

  1. Owen D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586-1593 (2021).
  2. Klemm T. et al. Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO J 39, e106275 (2020).
  3. Bader S. M., Cooney J. P. et al. SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates. Proc. Natl. Acad. Sci. 120, e2301689120 (2023).
  4. Bader S. M., Calleja D. J., Devine S. M., Kuchel N. W. et al. A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID. Nat. Commun. 16, 2900 (2025).