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Cross-resistance patterns in SARS-CoV-2 against 3CL protease inhibitors
Janice Chithelen1, David H Lovett1, Kevin Wang1
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Nature Communications
|May 19, 2026
Summary
Emerging SARS-CoV-2 resistance mutations threaten COVID-19 antiviral effectiveness. Understanding these mechanisms is crucial for developing new treatments against resistant viral strains.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is endemic, necessitating effective antiviral treatments.
- Small-molecule antivirals are critical for high-risk individuals, but resistance-conferring mutations are a growing concern.
- Understanding antiviral resistance mechanisms is vital for continued SARS-CoV-2 treatment efficacy.
Purpose of the Study:
- To investigate resistance pathways for SARS-CoV-2 3CL protease inhibitors: atilotrelvir, simnotrelvir, and ibuzatrelvir.
- To assess cross-resistance profiles among emerging SARS-CoV-2 variants and existing antivirals.
- To identify specific mutations conferring broad resistance to SARS-CoV-2 antivirals.
Main Methods:
- High-throughput viral passaging to generate resistant SARS-CoV-2 strains.
- Viral inhibition assays to quantify antiviral efficacy against evolved viruses.
- Cellular assays to determine the impact of specific mutations on viral resistance.
Main Results:
- Resistance to atilotrelvir, simnotrelvir, and ibuzatrelvir readily emerged through passaging.
- Significant overlap was observed in resistance mutations across different inhibitors.
- Broad cross-resistance was noted against nirmatrelvir and ensitrelvir, with mutations S144A, E166A, and E166V identified as key mediators, particularly E166V.
Conclusions:
- Emerging SARS-CoV-2 resistance mutations pose a significant threat to current antiviral therapies.
- Clinical management requires careful consideration of cross-resistance in salvage and combination therapies.
- Development of novel SARS-CoV-2 antivirals with alternative mechanisms is essential to combat resistance.
