Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19.
Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, Maruyama Y, Taoda Y, Kasamatsu K, Suto T, Kouki K, Nakahashi A, Kawashima S, Sanaki T, Toba S, Uemura K, Mizutare T, Ando S, Sasaki M, Orba Y, Sawa H, Sato A, Sato T, Kato T, Tachibana Y.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of <b>S-217622</b>, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. <b>S-217622</b> was 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. <b>S-217622</b> exhibited antiviral activity <i>in vitro</i> against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles <i>in vivo</i> for once-daily oral dosing. Furthermore, <b>S-217622</b> dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.