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

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 SaruwatariTadashi Okamura, Kenta Nakano, Shogo Misumi, Hiroaki Mitsuya, Hirokazu Tamamura

Disaster Medical Science Division

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	105365
Journal	iScience
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2022.105365
Publication status	Published - 2022 Nov 18

Keywords

Health sciences
Medical biochemistry
Pharmaceutical science
Virology

ASJC Scopus subject areas

General

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10.1016/j.isci.2022.105365

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Tsuji, K., Ishii, T., Kobayakawa, T., Higashi-Kuwata, N., Azuma, C., Nakayama, M., Onishi, T., Nakano, H., Wada, N., Hori, M., Shinohara, K., Miura, Y., Kawada, T., Hayashi, H., Hattori, S. I., Bulut, H., Das, D., Takamune, N., Kishimoto, N., ... Tamamura, H. (2022). Potent and biostable inhibitors of the main protease of SARS-CoV-2. iScience, 25(11), [105365]. https://doi.org/10.1016/j.isci.2022.105365

Tsuji, K, Ishii, T, Kobayakawa, T, Higashi-Kuwata, N, Azuma, C, Nakayama, M, Onishi, T, Nakano, H, Wada, N, Hori, M, Shinohara, K, Miura, Y, Kawada, T, Hayashi, H, Hattori, SI, Bulut, H, Das, D, Takamune, N, Kishimoto, N, Saruwatari, J, Okamura, T, Nakano, K, Misumi, S, Mitsuya, H & Tamamura, H 2022, 'Potent and biostable inhibitors of the main protease of SARS-CoV-2', iScience, vol. 25, no. 11, 105365. https://doi.org/10.1016/j.isci.2022.105365

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title = "Potent and biostable inhibitors of the main protease of SARS-CoV-2",

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",

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

note = "Funding Information: The authors thank Prof. Arun K. Ghosh, Purdue University, for his gift of 5h (2). This work was supported in part by Research Projects on COVID-19, Japan Agency for Medical Research and Development (AMED) 20fk0108510 (S.M. H.M. H.T.), JSPS KAKENHI Grant Numbers 20H03362 (H.T.), and AMED under Grant Numbers JP21am0101098 and JP22ama121043 (Platform Project for Supporting Drug Discovery and Life Science Research, BINDS) (H.T.). This research is based on the Cooperative Research Project of Research Center for Biomedical Engineering. The synchrotron radiation experiments at the SPring-8 beamline BL41XU were approved by the Japan Synchrotron Radiation Research Institute (Proposal No. 2021A2725). #K.T. T.I. and T.K. contributed equally to the study. K.T. T.I. T.K, N.H.-K. C.A. M.N. T.O. H.N. N.W. M.H. K.S. Y.M. T.K. S.H. N.T. N.K. T.O. K.N.: investigation; H.H. H.B. D.D. J.S.: analysis; S.M. H.M. H.T.: supervision; K.T. T.I. T.K. H.T.: writing. All authors have given approval to the final version of the manuscript. The authors declare no competing interests. Funding Information: The authors thank Prof. Arun K. Ghosh, Purdue University, for his gift of 5h ( 2 ). This work was supported in part by Research Projects on COVID-19, Japan Agency for Medical Research and Development (AMED) 20fk0108510 (S.M., H.M., H.T.), JSPS KAKENHI Grant Numbers 20H03362 (H.T.), and AMED under Grant Numbers JP21am0101098 and JP22ama121043 (Platform Project for Supporting Drug Discovery and Life Science Research, BINDS) (H.T.). This research is based on the Cooperative Research Project of Research Center for Biomedical Engineering. The synchrotron radiation experiments at the SPring-8 beamline BL41XU were approved by the Japan Synchrotron Radiation Research Institute (Proposal No. 2021A2725 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = nov,

day = "18",

doi = "10.1016/j.isci.2022.105365",

language = "English",

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T1 - Potent and biostable inhibitors of the main protease of SARS-CoV-2

AU - Tsuji, Kohei

AU - Ishii, Takahiro

AU - Kobayakawa, Takuya

AU - Higashi-Kuwata, Nobuyo

AU - Azuma, Chika

AU - Nakayama, Miyuki

AU - Onishi, Takato

AU - Nakano, Hiroki

AU - Wada, Naoya

AU - Hori, Miki

AU - Shinohara, Kouki

AU - Miura, Yutaro

AU - Kawada, Takuma

AU - Hayashi, Hironori

AU - Hattori, Shin ichiro

AU - Bulut, Haydar

AU - Das, Debananda

AU - Takamune, Nobutoki

AU - Kishimoto, Naoki

AU - Saruwatari, Junji

AU - Okamura, Tadashi

AU - Nakano, Kenta

AU - Misumi, Shogo

AU - Mitsuya, Hiroaki

AU - Tamamura, Hirokazu

N1 - Funding Information: The authors thank Prof. Arun K. Ghosh, Purdue University, for his gift of 5h (2). This work was supported in part by Research Projects on COVID-19, Japan Agency for Medical Research and Development (AMED) 20fk0108510 (S.M. H.M. H.T.), JSPS KAKENHI Grant Numbers 20H03362 (H.T.), and AMED under Grant Numbers JP21am0101098 and JP22ama121043 (Platform Project for Supporting Drug Discovery and Life Science Research, BINDS) (H.T.). This research is based on the Cooperative Research Project of Research Center for Biomedical Engineering. The synchrotron radiation experiments at the SPring-8 beamline BL41XU were approved by the Japan Synchrotron Radiation Research Institute (Proposal No. 2021A2725). #K.T. T.I. and T.K. contributed equally to the study. K.T. T.I. T.K, N.H.-K. C.A. M.N. T.O. H.N. N.W. M.H. K.S. Y.M. T.K. S.H. N.T. N.K. T.O. K.N.: investigation; H.H. H.B. D.D. J.S.: analysis; S.M. H.M. H.T.: supervision; K.T. T.I. T.K. H.T.: writing. All authors have given approval to the final version of the manuscript. The authors declare no competing interests. Funding Information: The authors thank Prof. Arun K. Ghosh, Purdue University, for his gift of 5h ( 2 ). This work was supported in part by Research Projects on COVID-19, Japan Agency for Medical Research and Development (AMED) 20fk0108510 (S.M., H.M., H.T.), JSPS KAKENHI Grant Numbers 20H03362 (H.T.), and AMED under Grant Numbers JP21am0101098 and JP22ama121043 (Platform Project for Supporting Drug Discovery and Life Science Research, BINDS) (H.T.). This research is based on the Cooperative Research Project of Research Center for Biomedical Engineering. The synchrotron radiation experiments at the SPring-8 beamline BL41XU were approved by the Japan Synchrotron Radiation Research Institute (Proposal No. 2021A2725 ). Publisher Copyright: © 2022 The Author(s)

PY - 2022/11/18

Y1 - 2022/11/18

N2 - 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.

AB - 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.

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KW - Medical biochemistry

KW - Pharmaceutical science

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

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