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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir
Sho Iketani1,2, Hiroshi Mohri1,2, Bruce Culbertson3,4
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Nature
|November 9, 2022
Summary
SARS-CoV-2 can readily develop resistance to nirmatrelvir, an oral antiviral for COVID-19. In vitro studies show multiple mutation pathways leading to resistance, highlighting the need for next-generation antiviral design.
Area of Science:
- Virology
- Antiviral Drug Resistance
- Molecular Biology
Background:
- Nirmatrelvir is an oral antiviral effective against SARS-CoV-2.
- Concerns exist regarding SARS-CoV-2 evolving resistance to nirmatrelvir, similar to other antivirals.
Purpose of the Study:
- To investigate the potential for SARS-CoV-2 to develop in vitro resistance to nirmatrelvir.
- To identify mutations and pathways associated with nirmatrelvir resistance.
Main Methods:
- In vitro passaging of SARS-CoV-2 in the presence of nirmatrelvir.
- Genomic sequencing to identify mutations in the 3CL protease.
- Construction and analysis of recombinant SARS-CoV-2 clones.
Main Results:
- Highly resistant SARS-CoV-2 variants emerged through multiple independent pathways.
- Mutations were observed at 23 different residues of the 3CL protease.
- Specific mutations like T21I, P252L, and T304I were common precursors, with E166V conferring significant resistance.
Conclusions:
- SARS-CoV-2 readily develops resistance to nirmatrelvir in vitro via diverse mutational routes.
- Understanding these resistance mechanisms is crucial for designing next-generation protease inhibitors.
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