A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID
Новый ингибитор PLpro улучшает исходы в доклинической модели длительного COVID-19
2025-04-03
SCID: 54.1/qbr37rq7
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SARS-CoV-2 PLpro inhibitorcoronavirus proteaselong COVIDmouse modelpost-acute sequelae of COVID-19
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Abstract (AI)
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.
Key Findings
1
A novel chemical scaffold targets SARS-CoV-2 PLpro with low-nanomolar inhibitory activity.
2
PLpro inhibition protects against multiple PASC-like symptoms, prevents lung pathology, and reduces brain dysfunction in mice, supporting clinical potential for long COVID prevention and treatment.
3
The lead compound demonstrates excellent in vivo efficacy in a mouse model of severe acute COVID-19.
4
The mouse model reproduces long-term pathologies closely resembling post-acute sequelae of COVID-19 (PASC).
5
The scaffold also inhibits PLpro from other pathogenic coronaviruses, indicating broader antiviral potential.
Research Object
SARS-CoV-2 infection and post-acute sequelae of COVID-19 (PASC) in a mouse model
Research Subject
The effects of PLpro inhibition by a novel inhibitor on acute disease, long-term PASC symptoms, lung pathology, and brain dysfunction
Publication Details
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2025-04-03
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