PLpro inhibition protects in post-acute sequelae mouse model of COVID-19

ABSTRACT: The COVID-19 pandemic has highlighted how vulnerable a globally connected population is to the threat of newly emerging zoonotic viruses, exemplified by SARS-CoV-2. Despite considerable efforts to identify antivirals for coronaviruses (CoVs) in the last two decades, there exists only one FDA-approved, effective drug, Paxlovid which targets the essential SARS-CoV-2 main protease. Whilst effective in the acute phase of the pandemic, Paxlovid cannot be used by all patients, can lead to viral recurrence, and has not demonstrated an effect on post-acute sequelae of COVID-19 (PASC), commonly known as Long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative orthogonal antivirals that are addressing broader patient needs, are urgently required. Herein we report our drug discovery efforts targeting PLpro, the second essential coronaviral protease, for which we have identified and developed a novel chemical scaffold that targets SARS-CoV-2 with low nanomolar activity. This chemical class also exhibits broad-spectrum activity against other pathogenic coronavirus PLpros. Our lead compound shows in vivo efficacy superior to Paxlovid in a mouse model of severe disease. Importantly, our mouse model of severe infection leads to long term pathologies matching closely those seen in PASC patients, including lung, heart, brain and gut dysfunctions. We show that our lead compound protects against long term lung and brain dysfunction in this model, whereas Paxlovid does not, providing a potential treatment option for PASC sufferers going forward.

INSTRUMENT(S): Orbitrap Astral

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Long Covid

SUBMITTER: Maria Tanzer  

LAB HEAD: David Komander

PROVIDER: PXD054356 | Pride | 2025-02-23

REPOSITORIES: Pride