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Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

2022; Cold Spring Harbor Laboratory; Linguagem: Inglês

10.1101/2022.01.26.477782

Yuto Unoh, Shota Uehara, Kenji Nakahara, Haruaki Nobori, Yukiko Yamatsu, Shiho Yamamoto, Yuki Maruyama, Yoshiyuki Taoda, Koji Kasamatsu, Takahiro Suto, Kensuke Kouki, Atsufumi Nakahashi, Sho Kawashima, Takao Sanaki, Shinsuke Toba, Kentaro Uemura, Tohru Mizutare, Shigeru Ando, Michihito Sasaki, Yasuko Orba, Hirofumi Sawa, Akihiko Sato, Takafumi Sato, Teruhisa Kato, Yuki Tachibana,

vaccines and immunoinformatics approaches

Abstract 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 S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 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. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.