Journal of medicinal chemistry · 2022
Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Unoh Yuto, Uehara Shota, Nakahara Kenji, Nobori Haruaki, Yamatsu Yukiko, Yamamoto Shiho, Maruyama Yuki, Taoda Yoshiyuki, Kasamatsu Koji, Suto Takahiro, Kouki Kensuke, Nakahashi Atsufumi, Kawashima Sho, Sanaki Takao, Toba Shinsuke, Uemura Kentaro, Mizutare Tohru, Ando Shigeru, Sasaki Michihito, Orba Yasuko, Sawa Hirofumi, Sato Akihiko, Sato Takafumi, Kato Teruhisa, Tachibana Yuki
Аннотация
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 noncovalent, nonpeptidic 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 noncovalent inhibitor could be a potential oral agent for treating COVID-19.