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Updated: May 22, 2026
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Reverse Genetics to Engineer Positive-Sense RNA Virus Variants
Published on: June 9, 2022
Cell-type specific effects of SARS-CoV-2 P252L mutation on nirmatrelvir sensitivity
Sheryline Loison1, Mehdi Chabert1, Constant Gensous1
1Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, Geneva, 1206, Switzerland.
Antiviral Research
|May 20, 2026
Summary
The SARS-CoV-2 P252L mutation’s impact on Nirmatrelvir (NTV) drug resistance varies by cell model. Functional resistance was observed only in VeroE6 cells, not Calu-3 or HAE cultures, emphasizing model selection importance.
Area of Science:
- Virology
- Drug Resistance Studies
- Molecular Biology
Background:
- The SARS-CoV-2 main protease (NSP5) is a key target for the antiviral Nirmatrelvir (NTV).
- The P252L mutation in NSP5 has been observed in clinical isolates, prompting investigation into its role in NTV drug resistance.
Purpose of the Study:
- To investigate the effect of the NSP5 P252L mutation on Nirmatrelvir (NTV) susceptibility across different cell culture models.
- To determine if observed allelic selection correlates with functional drug resistance.
Main Methods:
- Spontaneous mutation analysis in VeroE6 and Calu-3 cells.
- Enrichment of the P252L mutation under NTV pressure in VeroE6 and Human Airway Epithelium (HAE) cultures.
- Determination of EC50 values to assess NTV susceptibility.
Main Results:
- The P252L mutation arose spontaneously in VeroE6 cells but not Calu-3 cells.
- NTV pressure enriched the P252L mutation in VeroE6 and HAE cultures.
- A significant increase in EC50 values (indicating reduced susceptibility) was observed only in VeroE6 cells.
Conclusions:
- The functional impact of the NSP5 P252L mutation on NTV resistance is cell-model dependent.
- Discrepancies between allelic selection and functional resistance underscore the need for appropriate cell models in resistance studies.
