Focus on SARS-CoV-2 Proteases: Structure, Function, and Inhibitor Development

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a β-coronavirus within the Coronaviridae family, revealed substantial limitations in existing antiviral strategies and global preparedness for emerging viral infections. During the pandemic, SARS-CoV-2 developed rapidly into several variants due to its natural evolution during infection and replication; furthermore, the treatment with drugs induced the mutant selection of the virus. Taken together, these factors led to the continuous outbreaks of new variants, highlighting the urgent need for the development of more efficacious and broad-spectrum antiviral agents. In this context, viral proteases, the Main (Mpro) and the Papain-like (PLpro) proteases, are essential enzymes for coronavirus (CoV) replication, which emerged as two of the most attractive and explored therapeutic targets to identify potent and selective CoV inhibitors. The chapter describes the approved SARS-CoV-2 Mpro inhibitors and the most recent and promising agents in development targeting both the Mpro and PLpro, highlighting the similarities and differences with the other relevant CoV proteases, such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS), emphasizing the challenges and the potential to develop broad-spectrum antiviral CoV agents.