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

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

  • Nat Commun. 2023 Feb 25;14(1):1076. doi: 10.1038/s41467-023-36729-0.
Nobuyo Higashi-Kuwata 1,  Kohei Tsuji 2,  Hironori Hayashi 3,  Haydar Bulut 4,  Maki Kiso 5,  Masaki Imai 5 6,  Hiromi Ogata-Aoki 4,  Takahiro Ishii 2,  Takuya Kobayakawa 2,  Kenta Nakano 7,  Nobutoki Takamune 8,  Naoki Kishimoto 8,  Shin-Ichiro Hattori 1,  Debananda Das 4,  Yukari Uemura 9,  Yosuke Shimizu 9,  Manabu Aoki 4,  Kazuya Hasegawa 10,  Satoshi Suzuki 11,  Akie Nishiyama 11,  Junji Saruwatari 12,  Yukiko Shimizu 7,  Yoshikazu Sukenaga 1,  Yuki Takamatsu 1,  Kiyoto Tsuchiya 13,  Kenji Maeda 1,  Kazuhisa Yoshimura 14,  Shun Iida 15,  Seiya Ozono 15,  Tadaki Suzuki 15,  Tadashi Okamura 7,  Shogo Misumi 8,  Yoshihiro Kawaoka 5 6 16,  Hirokazu Tamamura 2,  Hiroaki Mitsuya 17 18 19
Affiliations

Affiliations

  • 1 Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 2 Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
  • 3 Department of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • 4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 5 Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 6 The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 7 Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • 8 Department of Environmental and Molecular Health Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • 9 Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
  • 10 Structural Biology Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
  • 11 Department of Infectious Diseases, Tohoku University Graduate School of Medicine, Miyagi, Japan.
  • 12 Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
  • 13 AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
  • 14 Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
  • 15 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
  • 16 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • 17 Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. hmitsuya@hosp.ncgm.go.jp.
  • 18 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, NIH, Bethesda, MD, USA. hmitsuya@hosp.ncgm.go.jp.
  • 19 Kumamoto University Hospital, Kumamoto, Japan. hmitsuya@hosp.ncgm.go.jp.
PMID: 36841831 DOI: 10.1038/s41467-023-36729-0
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.

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