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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir
Biorxiv : the Preprint Server for Biology
|August 29, 2022
Summary
SARS-CoV-2 can readily develop resistance to nirmatrelvir, an oral antiviral. In vitro studies show multiple mutations in the 3CL protease lead to resistance, informing future antiviral drug design.
Area of Science:
- Virology
- Drug Resistance
- Molecular Biology
Background:
- Nirmatrelvir is an oral antiviral effective against SARS-CoV-2, reducing COVID-19 hospitalizations.
- Concerns exist regarding SARS-CoV-2 evolving resistance to nirmatrelvir, similar to other antivirals.
- Understanding resistance mechanisms is crucial for developing next-generation therapeutics.
Approach:
- SARS-CoV-2 was passaged in vitro with increasing nirmatrelvir concentrations using two independent methods.
- High-throughput screening in 480 wells identified multiple resistant viral lineages.
- Genomic sequencing identified numerous mutations in the 3CL protease enzyme.
Key Points:
- Multiple mutational pathways to nirmatrelvir resistance were observed, with T21I, P252L, and T304I identified as common precursor mutations.
- Low-level resistance was mediated by single mutations, while high-level resistance required accumulated mutations.
- The E166V mutation conferred significant resistance but reduced viral fitness, which was restored by compensatory mutations.
Conclusions:
- SARS-CoV-2 readily develops resistance to nirmatrelvir through various in vitro pathways.
- Identified mutations provide a basis for studying resistance mechanisms and designing improved protease inhibitors.
- Cross-resistance patterns with other protease inhibitors like ensitrelvir were investigated.
