2. Academic Validation
  3. Cell-type specific effects of SARS-CoV-2 P252L mutation on nirmatrelvir sensitivity

Cell-type specific effects of SARS-CoV-2 P252L mutation on nirmatrelvir sensitivity

  • Antiviral Res. 2026 Jul:251:106445. doi: 10.1016/j.antiviral.2026.106445.
Sheryline Loison 1,  Mehdi Chabert 1,  Constant Gensous 1,  Samuel Constant 2,  Song Huang 2,  Caroline Tapparel 1,  Sophie Clément 3
Affiliations

Affiliations

  • 1 Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, Geneva, 1206, Switzerland.
  • 2 Epithelix Sarl, 18 chemin des Aulx, Plan-les-Ouates, 1228, Switzerland.
  • 3 Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel-Servet, Geneva, 1206, Switzerland. Electronic address: [email protected].
PMID: 42162876 DOI: 10.1016/j.antiviral.2026.106445
Abstract

The SARS-CoV-2 main protease (NSP5) is the target of the FDA approved Nirmatrelvir (NTV) Antiviral. Substitutions in NSP5, such as the P252L mutation, have been reported in clinical isolates and raise questions regarding its potential role in drug resistance. Here, we show that the P252L effect on NTV susceptibility is dependent on the culture model. The mutation arises spontaneously in VeroE6 cells without treatment but does not appear in Calu-3 cells. It becomes enriched under NTV pressure in both VeroE6 cells and Human Airway Epithelium (HAE) cultures but leads to a significant increase in EC50 values only in VeroE6 cells. This discrepancy between allelic selection and functional resistance highlights the importance of using appropriate culture models when evaluating resistance mechanisms.

Keywords

Drug resistance; HAE culture; NSP5 protease; Nirmatrelvir; SARS-CoV-2.

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