jm1c00665_si_001.pdf (1.62 MB)
3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV‑2 Agents
journal contribution
posted on 2021-07-27, 14:37 authored by Sho Konno, Kiyotaka Kobayashi, Miki Senda, Yuta Funai, Yuta Seki, Ikumi Tamai, Laura Schäkel, Kyousuke Sakata, Thanigaimalai Pillaiyar, Akihiro Taguchi, Atsuhiko Taniguchi, Michael Gütschow, Christa E. Müller, Koh Takeuchi, Mikako Hirohama, Atsushi Kawaguchi, Masaki Kojima, Toshiya Senda, Yoshiyuki Shirasaka, Wataru Kamitani, Yoshio HayashiThe
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.
