Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CLProtease Inhibitor Clinical Candidate for Treating COVID-19 br

The coronavirus disease 2019 (COVID-19) pandemic, caused bysevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted inmillions of deaths and threatens public health and safety. Despite the rapid globalspread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed.Here, we describe the discovery ofS-217622, thefirst oral noncovalent,nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate.S-217622was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy.S-217622exhibited antiviral activityin vitroagainstcurrent outbreaking SARS-CoV-2 variants and showed favorable pharmacokineticprofilesin vivofor once-daily oral dosing. Furthermore,S-217622dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice,indicating that this novel noncovalent inhibitor could be a potential oral agent fortreating COVID-19.