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

Sci Transl Med. 2023 Jan 18;15(679):eabq4064. doi: 10.1126/scitranslmed.abq4064. Epub 2023 Jan 18.


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 submicromolar 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, 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), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19*
  • Cricetinae
  • Humans
  • Prospective Studies
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2
  • Viral Load
  • Viral Nonstructural Proteins


  • 3C-like proteinase, SARS-CoV-2
  • ensitrelvir
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Antiviral Agents

Supplementary concepts

  • SARS-CoV-2 variants