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

Author

Listed:
  • 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
    National Center for Global Health and Medicine Research Institute)

  • 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
    National Center for Global Health and Medicine Research Institute
    University of Wisconsin-Madison)

  • Hirokazu Tamamura

    (Tokyo Medical and Dental University)

  • Hiroaki Mitsuya

    (National Center for Global Health and Medicine Research Institute
    National Cancer Institute, NIH
    Kumamoto University Hospital)

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.

Suggested Citation

  • 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 Kish, 2023. "Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36729-0
    DOI: 10.1038/s41467-023-36729-0
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    References listed on IDEAS

    as
    1. Shin-ichiro Hattori & Nobuyo Higashi-Kuwata & Hironori Hayashi & Srinivasa Rao Allu & Jakka Raghavaiah & Haydar Bulut & Debananda Das & Brandon J. Anson & Emma K. Lendy & Yuki Takamatsu & Nobutoki Tak, 2021. "A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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    3. Yunlong Cao & Ayijiang Yisimayi & Fanchong Jian & Weiliang Song & Tianhe Xiao & Lei Wang & Shuo Du & Jing Wang & Qianqian Li & Xiaosu Chen & Yuanling Yu & Peng Wang & Zhiying Zhang & Pulan Liu & Ran A, 2022. "BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection," Nature, Nature, vol. 608(7923), pages 593-602, August.
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