2. Academic Validation
  3. Assessment of the frequency of SARS-CoV-2 Omicron variant escape from RNA-dependent RNA polymerase inhibitors and 3C-like protease inhibitors

Assessment of the frequency of SARS-CoV-2 Omicron variant escape from RNA-dependent RNA polymerase inhibitors and 3C-like protease inhibitors

  • Antiviral Res. 2023 Jul 12;105671. doi: 10.1016/j.antiviral.2023.105671.
Emi Takashita 1,  Seiichiro Fujisaki 2,  Hiroko Morita 2,  Shiho Nagata 2,  Hideka Miura 2,  Mami Nagashima 3,  Shinji Watanabe 2,  Makoto Takeda 4,  Yoshihiro Kawaoka 5,  Hideki Hasegawa 2
Affiliations

Affiliations

  • 1 Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan. Electronic address: [email protected].
  • 2 Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
  • 3 Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku-ku, Tokyo, 169-0073, Japan.
  • 4 Department of Virology Ⅲ, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan; Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 5 Division of Virology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan; Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan; Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI, 53711, USA; The University of Tokyo, Pandemic Preparedness, Infection, and Advanced Research Center, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
PMID: 37451629 DOI: 10.1016/j.antiviral.2023.105671
Abstract

The emergence and spread of antiviral-resistant SARS-CoV-2 is of great concern. In this study, we evaluated the propensity of Omicron variants to escape from RNA-dependent RNA polymerase (RdRP) inhibitors and 3C-like protease (3CLpro) inhibitors. SARS-CoV-2 Delta and Omicron variants were serially passaged in vitro in the presence of RdRP inhibitors (remdesivir and molnupiravir) and 3CLpro inhibitors (nirmatrelvir and lufotrelvir) to detect SARS-CoV-2 escape mutants. After five passages with 3CLpro inhibitors, mutant viruses that escaped from 3CLpro inhibitors emerged; however, in the presence of RdRP inhibitors all variants disappeared within 2-4 passages. Our findings suggest that the frequency of SARS-CoV-2 mutant escape from RdRP inhibitors is lower than that from 3CLpro inhibitors. We also found that Delta variants were more likely to acquire amino acid substitutions associated with resistance to 3CLpro inhibitors under the selective pressure of this drug compared with Omicron variants.

Keywords

Lufotrelvir; Molnupiravir; Nirmatrelvir; Remdesivir; Resistance; SARS-CoV-2.

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