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
  • 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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