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

Kohei Tsuji; Takahiro Ishii; Takuya Kobayakawa; Nobuyo Higashi-Kuwata; Chika Azuma; Miyuki Nakayama; Takato Onishi; Hiroki Nakano; Naoya Wada; Miki Hori; Kouki Shinohara; Yutaro Miura; Takuma Kawada; Hironori Hayashi; Shin-Ichiro Hattori; Haydar Bulut; Debananda Das; Nobutoki Takamune; Naoki Kishimoto; Junji Saruwatari; Tadashi Okamura; Kenta Nakano; Shogo Misumi; Hiroaki Mitsuya; Hirokazu Tamamura

doi:10.1016/j.isci.2022.105365

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. Epub 2022 Nov 1.

Authors

Kohei Tsuji¹, Takahiro Ishii¹, Takuya Kobayakawa¹, Nobuyo Higashi-Kuwata², Chika Azuma¹, Miyuki Nakayama¹, Takato Onishi¹, Hiroki Nakano¹, Naoya Wada¹, Miki Hori¹, Kouki Shinohara¹, Yutaro Miura¹, Takuma Kawada¹, Hironori Hayashi³, Shin-Ichiro Hattori², Haydar Bulut⁴, Debananda Das⁴, Nobutoki Takamune⁵, Naoki Kishimoto⁵, Junji Saruwatari⁶, Tadashi Okamura⁷, Kenta Nakano⁷, Shogo Misumi⁵, Hiroaki Mitsuya^{2

4

8}, Hirokazu Tamamura¹

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.

Abstract

Potent and biostable inhibitors of the main protease (M^pro) 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 M^pro 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.