2. Academic Validation
  3. Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease of SARS-CoV-2

  • iScience. 2022 Nov 18;25(11):105365. doi: 10.1016/j.isci.2022.105365.
Kohei Tsuji 1,  Takahiro Ishii 1,  Takuya Kobayakawa 1,  Nobuyo Higashi-Kuwata 2,  Chika Azuma 1,  Miyuki Nakayama 1,  Takato Onishi 1,  Hiroki Nakano 1,  Naoya Wada 1,  Miki Hori 1,  Kouki Shinohara 1,  Yutaro Miura 1,  Takuma Kawada 1,  Hironori Hayashi 3,  Shin-Ichiro Hattori 2,  Haydar Bulut 4,  Debananda Das 4,  Nobutoki Takamune 5,  Naoki Kishimoto 5,  Junji Saruwatari 6,  Tadashi Okamura 7,  Kenta Nakano 7,  Shogo Misumi 5,  Hiroaki Mitsuya 2 4 8,  Hirokazu Tamamura 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan.
  • 2 Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 3 Department of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Aoba-ku, Sendai 980-8572, Japan.
  • 4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Department of Environmental and Molecular Health Sciences, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan.
  • 6 Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan.
  • 7 Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 8 Department of Clinical Sciences, Kumamoto University Hospital, Chuo-ku, Kumamoto 860-8556, Japan.
PMID: 36338434 DOI: 10.1016/j.isci.2022.105365
Abstract

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 Infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Keywords

Health sciences; Medical biochemistry; Pharmaceutical science; Virology.

Figures
Products