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

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 and Hiroaki Mitsuya ()
Additional contact information
Nobuyo Higashi-Kuwata: National Center for Global Health and Medicine Research Institute
Kohei Tsuji: Tokyo Medical and Dental University
Hironori Hayashi: Tohoku University
Haydar Bulut: National Cancer Institute, NIH
Maki Kiso: University of Tokyo
Masaki Imai: University of Tokyo
Hiromi Ogata-Aoki: National Cancer Institute, NIH
Takahiro Ishii: Tokyo Medical and Dental University
Takuya Kobayakawa: Tokyo Medical and Dental University
Kenta Nakano: National Center for Global Health and Medicine
Nobutoki Takamune: Kumamoto University
Naoki Kishimoto: Kumamoto University
Shin-ichiro Hattori: National Center for Global Health and Medicine Research Institute
Debananda Das: National Cancer Institute, NIH
Yukari Uemura: National Center for Global Health and Medicine
Yosuke Shimizu: National Center for Global Health and Medicine
Manabu Aoki: National Cancer Institute, NIH
Kazuya Hasegawa: Japan Synchrotron Radiation Research Institute
Satoshi Suzuki: Tohoku University Graduate School of Medicine
Akie Nishiyama: Tohoku University Graduate School of Medicine
Junji Saruwatari: Kumamoto University
Yukiko Shimizu: National Center for Global Health and Medicine
Yoshikazu Sukenaga: National Center for Global Health and Medicine Research Institute
Yuki Takamatsu: National Center for Global Health and Medicine Research Institute
Kiyoto Tsuchiya: National Center for Global Health and Medicine
Kenji Maeda: National Center for Global Health and Medicine Research Institute
Kazuhisa Yoshimura: Tokyo Metropolitan Institute of Public Health
Shun Iida: National Institute of Infectious Diseases
Seiya Ozono: National Institute of Infectious Diseases
Tadaki Suzuki: National Institute of Infectious Diseases
Tadashi Okamura: National Center for Global Health and Medicine
Shogo Misumi: Kumamoto University
Yoshihiro Kawaoka: University of Tokyo
Hirokazu Tamamura: Tokyo Medical and Dental University
Hiroaki Mitsuya: National Center for Global Health and Medicine Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro’s active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36729-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36729-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36729-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().