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Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

Michihito Sasaki, Koshiro Tabata, Mai Kishimoto, Yukari Itakura, Hiroko Kobayashi, Takuma Ariizumi, Kentaro Uemura, Shinsuke Toba, Shinji Kusakabe, Yuki Maruyama, Shun Iida, Noriko Nakajima, Tadaki Suzuki, Shinpei Yoshida, Haruaki Nobori, Takao Sanaki, Teruhisa Kato, Takao Shishido, William W. Hall, Yasuko Orba, Akihiko Sato, Hirofumi Sawa
doi: https://doi.org/10.1101/2022.02.14.480338
Michihito Sasaki
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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  • For correspondence: m-sasaki@czc.hokudai.ac.jp h-sawa@czc.hokudai.ac.jp
Koshiro Tabata
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Mai Kishimoto
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Yukari Itakura
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Hiroko Kobayashi
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Takuma Ariizumi
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Kentaro Uemura
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
2Shionogi & Co., Ltd., Osaka, Japan
3Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan
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Shinsuke Toba
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
2Shionogi & Co., Ltd., Osaka, Japan
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Shinji Kusakabe
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
2Shionogi & Co., Ltd., Osaka, Japan
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Yuki Maruyama
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
2Shionogi & Co., Ltd., Osaka, Japan
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Shun Iida
4Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
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Noriko Nakajima
4Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
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Tadaki Suzuki
4Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
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Shinpei Yoshida
2Shionogi & Co., Ltd., Osaka, Japan
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Haruaki Nobori
2Shionogi & Co., Ltd., Osaka, Japan
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Takao Sanaki
2Shionogi & Co., Ltd., Osaka, Japan
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Teruhisa Kato
2Shionogi & Co., Ltd., Osaka, Japan
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Takao Shishido
2Shionogi & Co., Ltd., Osaka, Japan
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William W. Hall
5International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
6National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland
7Global Virus Network, Baltimore, Maryland, USA
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Yasuko Orba
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
5International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
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Akihiko Sato
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
2Shionogi & Co., Ltd., Osaka, Japan
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Hirofumi Sawa
1Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
5International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
7Global Virus Network, Baltimore, Maryland, USA
8One Health Research Center, Hokkaido University, Sapporo, Japan
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  • For correspondence: m-sasaki@czc.hokudai.ac.jp h-sawa@czc.hokudai.ac.jp
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Abstract

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622, a novel inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates the disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S-217622 demonstrated eminent pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron variant. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

Competing Interest Statement

The authors K.U., S.T., S.K., Y.M., S.Y., H.N., T. Sanaki, T.K., T.Shishido and A.S., are employees of Shionogi & Co., Ltd. Shionogi & Co., Ltd. and Hokkaido University have applied for patent applications covering S-217622 as well as related compounds. The remaining authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 15, 2022.
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Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19
Michihito Sasaki, Koshiro Tabata, Mai Kishimoto, Yukari Itakura, Hiroko Kobayashi, Takuma Ariizumi, Kentaro Uemura, Shinsuke Toba, Shinji Kusakabe, Yuki Maruyama, Shun Iida, Noriko Nakajima, Tadaki Suzuki, Shinpei Yoshida, Haruaki Nobori, Takao Sanaki, Teruhisa Kato, Takao Shishido, William W. Hall, Yasuko Orba, Akihiko Sato, Hirofumi Sawa
bioRxiv 2022.02.14.480338; doi: https://doi.org/10.1101/2022.02.14.480338
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Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19
Michihito Sasaki, Koshiro Tabata, Mai Kishimoto, Yukari Itakura, Hiroko Kobayashi, Takuma Ariizumi, Kentaro Uemura, Shinsuke Toba, Shinji Kusakabe, Yuki Maruyama, Shun Iida, Noriko Nakajima, Tadaki Suzuki, Shinpei Yoshida, Haruaki Nobori, Takao Sanaki, Teruhisa Kato, Takao Shishido, William W. Hall, Yasuko Orba, Akihiko Sato, Hirofumi Sawa
bioRxiv 2022.02.14.480338; doi: https://doi.org/10.1101/2022.02.14.480338

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