2. Academic Validation
  3. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

  • Sci Transl Med. 2022 Nov 3;eabq4064. doi: 10.1126/scitranslmed.abq4064.
Michihito Sasaki 1,  Koshiro Tabata 1,  Mai Kishimoto 1,  Yukari Itakura 1,  Hiroko Kobayashi 1,  Takuma Ariizumi 1,  Kentaro Uemura 1 2 3,  Shinsuke Toba 1 2,  Shinji Kusakabe 1 2,  Yuki Maruyama 1 2,  Shun Iida 4,  Noriko Nakajima 4,  Tadaki Suzuki 4,  Shinpei Yoshida 2,  Haruaki Nobori 2,  Takao Sanaki 2,  Teruhisa Kato 2,  Takao Shishido 2,  William W Hall 5 6 7,  Yasuko Orba 1 5,  Akihiko Sato 1 2 8,  Hirofumi Sawa 1 5 7 8 9
Affiliations

Affiliations

  • 1 Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, 001-220, Japan.
  • 2 Shionogi & Co., Ltd., Osaka 561-0825, Japan.
  • 3 Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, 060-0812, Japan.
  • 4 Department of Pathology, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan.
  • 5 International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, 001-0020, Japan.
  • 6 National Virus Reference Laboratory, School of Medicine, University College of Dublin, 4, Ireland.
  • 7 Global Virus Network, Baltimore, MD, 21201, USA.
  • 8 Institute for Vaccine Research and Development (IVReD), Hokkaido University, Sapporo, 001-0021, Japan.
  • 9 One Health Research Center, Hokkaido University, Sapporo, 001-0020, Japan.
PMID: 36327352 DOI: 10.1126/scitranslmed.abq4064
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 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates 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 favorable 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 BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an Antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), possesses remarkable Antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

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