The Same and Not the Same: Discovery of S-892216, A Second-Generation Nonpeptidic Covalent 3CL Protease Inhibitor for Oral COVID-19 Therapeutics.

The COVID-19 pandemic underscored the critical need for effective antiviral therapeutics. While vaccines have been instrumental in mitigating disease severity, the emergence of variants and long-COVID symptoms highlight the ongoing importance of antiviral therapeutic interventions. Targeting the 3CLpro main protease has been successful in identifying clinical agents; however limited options exist, and improvements are still required to have broader clinical utility. Utilizing the established central scaffold to develop ensitrelvir, both noncovalent and covalent modes of action were leveraged using structural knowledge to identify S-892216 as a potential best-in-class reversible covalent nonpeptidic 3CLpro inhibitor with a superior preclinical profile for treatment of COVID-19 and future pandemic preparedness.