2. Academic Validation
  3. In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir

In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir

  • Nat Commun. 2023 Jul 15;14(1):4231. doi: 10.1038/s41467-023-40018-1.
Maki Kiso 1,  Seiya Yamayoshi 2 3 4,  Shun Iida 5,  Yuri Furusawa 1 6,  Yuichiro Hirata 5,  Ryuta Uraki 1 6,  Masaki Imai 1 7 6,  Tadaki Suzuki 5,  Yoshihiro Kawaoka 8 9 10 11
Affiliations

Affiliations

  • 1 Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 2 Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. yamayo@ims.u-tokyo.ac.jp.
  • 3 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan. yamayo@ims.u-tokyo.ac.jp.
  • 4 The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. yamayo@ims.u-tokyo.ac.jp.
  • 5 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
  • 6 The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 7 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 8 Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu.
  • 9 The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu.
  • 10 The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu.
  • 11 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. yoshihiro.kawaoka@wisc.edu.
PMID: 37454219 DOI: 10.1038/s41467-023-40018-1
Abstract

Ensitrelvir, an oral Antiviral agent that targets a SARS-CoV-2 main Protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to most monoclonal antibody therapies, SARS-CoV-2 resistance to other antivirals including main Protease Inhibitors such as ensitrelvir is a major public health concern. Here, repeating passages of SARS-CoV-2 in the presence of ensitrelvir revealed that the M49L and E166A substitutions in Nsp5 are responsible for reduced sensitivity to ensitrelvir. Both substitutions reduced in vitro virus growth in the absence of ensitrelvir. The combination of the M49L and E166A substitutions allowed the virus to largely evade the suppressive effect of ensitrelvir in vitro. The virus possessing Nsp5-M49L showed similar pathogenicity to wild-type virus, whereas the virus possessing Nsp5-E166A or Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment of hamsters infected with the virus possessing Nsp5-M49L/E166A was ineffective; however, nirmatrelvir or molnupiravir treatment was effective. Therefore, it is important to closely monitor the emergence of ensitrelvir-resistant SARS-CoV-2 variants to guide Antiviral treatment selection.

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