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

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• The COVID-19 pandemic underscores the threat of zoonotic viruses.
• Paxlovid, an FDA-approved antiviral, targets SARS-CoV-2 Mpro but has limitations, including patient eligibility and lack of protection against long COVID.
• There is an urgent need for alternative antivirals addressing broader patient needs and long COVID.

Purpose of the Study:

• To identify novel chemical scaffolds targeting the SARS-CoV-2 papain-like protease (PLpro).
• To evaluate the efficacy of a lead compound against severe acute disease and long COVID pathologies.
• To explore the potential of PLpro inhibition for preventing and treating post-acute sequelae of COVID-19 (PASC).

Main Methods:

• Drug discovery efforts focused on identifying novel chemical scaffolds targeting SARS-CoV-2 PLpro.
• In vitro assays were used to determine the activity of compounds against SARS-CoV-2 PLpro and other pathogenic coronaviruses.
• In vivo studies utilized a mouse model of severe acute COVID-19 that recapitulates long-term pathologies similar to PASC.

Main Results:

• A novel chemical scaffold targeting SARS-CoV-2 PLpro was identified with low nanomolar activity.
• The lead compound demonstrated broad activity against PLpro from other pathogenic coronaviruses.
• The lead compound showed excellent in vivo efficacy in a mouse model, protecting against severe acute disease and PASC-like symptoms, including lung pathology and brain dysfunction.

Conclusions:

• PLpro is a viable therapeutic target for both acute COVID-19 and PASC.
• The novel lead compound offers a promising therapeutic strategy for addressing the unmet medical needs in COVID-19 and PASC.
• PLpro inhibition represents a potential clinical approach for PASC prevention and treatment.