Journal of medicinal chemistry · 2021
3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Konno Sho, Kobayashi Kiyotaka, Senda Miki, Funai Yuta, Seki Yuta, Tamai Ikumi, Schäkel Laura, Sakata Kyousuke, Pillaiyar Thanigaimalai, Taguchi Akihiro, Taniguchi Atsuhiko, Gütschow Michael, Müller Christa E, Takeuchi Koh, Hirohama Mikako, Kawaguchi Atsushi, Kojima Masaki, Senda Toshiya, Shirasaka Yoshiyuki, Kamitani Wataru, Hayashi Yoshio
Аннотация
The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.