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Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2

Medicine and Health

Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2

N. Higashi-kuwata, K. Tsuji, et al.

Researchers Nobuyo Higashi-Kuwata and colleagues have discovered two novel small molecules, TKB245 and TKB248, that effectively inhibit the main protease of SARS-CoV-2, demonstrating superior efficacy over existing treatments. These groundbreaking compounds offer a potential avenue for COVID-19 therapeutics by blocking infectivity and replication of the virus, along with its Delta and Omicron variants.

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Playback language: English
Abstract
COVID-19 caused by SARS-CoV-2 has continually been a serious threat to public health worldwide. Two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, specifically inhibit SARS-CoV-2 main protease (Mpro) activity and potently block SARS-CoV-2 infectivity and replication more effectively than nirmatrelvir, molnupiravir, and ensitrelvir. Both compounds also block Delta and Omicron variant replication in human-ACE2-knocked-in mice. Native mass spectrometry shows binding to dimer Mpro, promoting dimerization. X-ray crystallography reveals binding to Mpro's active site, forming a covalent bond with Cys-145. These compounds show potential as COVID-19 therapeutics.
Publisher
Nature Communications
Published On
Feb 25, 2023
Authors
Nobuyo Higashi-Kuwata, Kohei Tsuji, Hironori Hayashi, Haydar Bulut, Maki Kiso, Masaki Imai, Hiromi Ogata-Aoki, Takahiro Ishii, Takuya Kobayakawa, Kenta Nakano, Nobutoki Takamune, Naoki Kishimoto, Shin-ichiro Hattori, Debananda Das, Yukari Uemura, Yosuke Shimizu, Manabu Aoki, Kazuya Hasegawa, Satoshi Suzuki, Akie Nishiyama, Junji Saruwatari, Yukiko Shimizu, Yoshikazu Sukenaga, Yuki Takamatsu, Kiyoto Tsuchiya, Kenji Maeda, Kazuhisa Yoshimura, Shun Iida, Seiya Ozono, Tadaki Suzuki, Tadashi Okamura, Shogo Misumi, Yoshihiro Kawaoka, Hirokazu Tamamura, Hiroaki Mitsuya
Tags
COVID-19
SARS-CoV-2
main protease
inhibition
therapeutics
variants
small molecules

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