A novel PLpro inhibitor scaffold that protects mice from Long-COVID

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The only FDA-approved coronavirus antiviral, Paxlovid, 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. 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, 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.