The COVID-19 pandemic, caused by SARS-CoV-2, led to an urgent search for effective antiviral treatments. One of the most widely used is Nirmatrelvir, the key component of Paxlovid, which targets the viral protease, NSP5. This enzyme is crucial for viral replication, as it cleaves viral polyproteins into functional parts.
However, like with other antivirals, resistance mutations can reduce Nirmatrelvir long-term effectiveness. These mutations may change the conformation of the protease, making it harder for the drug to bind and block its activity. Several mutations have been found to lower Nirmatrelvir’s effectiveness to different degrees.
The P252L mutation, while conferring only low-level resistance on its own, may promote the emergence of additional mutations that enhance resistance (Iketani et al. ). Listed by the FDA as selected by Nirmatrelvir in vitro, P542L has also been observed in patients. In a study of patients who had viral rebound after treatment, it was detected alongside E166V and V297A, but all appeared in less than 2% of the virus population and transiently, suggesting limited clinical relevance (JAMA Network).
These findings highlight the limitations of in vitro studies using cell lines like Vero or Calu-3, which do not fully mimic the human airway and could favor adaptation mutations.
