ArticleScience advances2022
Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system.
Article in Science advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 154 papers.
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Who cites it
154 citing papers in PubMed, 216 citations in OpenAlex.
- Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.EBioMedicine · 2025Trial
- Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1).The Journal of infectious diseases · 2023Trial
- Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990.bioRxiv : the preprint server for biology · 2026Article
- Nitrile-Based Inhibitors Targeting both SARS-CoV‑2 Main Protease and Human Cathepsin L.ACS medicinal chemistry letters · 2026Article
- The Combination of Nirmatrelvir and Ivermectin Exerts Strongly Synergistic Antiviral and Anti-Inflammatory Effects Against Murine Coronavirus Infection of Macrophages.International journal of molecular sciences · 2026Article
- Heat Shock Protein Inhibitor Tanespimycin (17AAG) Suppresses SARS-CoV-2 Main Protease Activity and Is More Potent Than Clinically Approved Antiviral Nirmatrelvir.Chembiochem : a European journal of chemical biology · 2026Article
- Article
- Identification of spiropyrrolidinoxindoles as SARS-CoV-2 main protease inhibitor hits from virtual screening.Journal of computer-aided molecular design · 2026Article
- VPS34 inhibition as a host-targeting anti-coronaviral strategy: Rational design of YBM with optimized pharmacokinetic parameters.Acta pharmaceutica Sinica. B · 2026Article
- Inhibitory effects and structural analysis of drug candidate PF-07817883 against coronaviral main proteases (MJournal of structural biology: X · 2026Article
- SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir.Journal of virology · 2026Article
- Cross-resistance patterns in SARS-CoV-2 against 3CL protease inhibitors.Nature communications · 2026Article
- Antagonistic Ubiquitin Switching by USP7 and RNF40 Orchestrates KDM6A Homeostasis to License Coronavirus Susceptibility.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum.Nature communications · 2026Article
- Characterization of the Cross-Resistance of SARS-CoV‑2 Main Protease Inhibitors, Ibuzatrelvir, Ensitrelvir, and Nirmatrelvir.ACS pharmacology & translational science · 2026Article
- Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structure-Based Design of Covalent SARS-CoV‑2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants.JACS Au · 2026Article
- Article
- SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots.Emerging microbes & infections · 2025Article
- Preclinical characterization of EGT710, an oral non-peptidomimetic reversible covalent SARS-CoV-2 main protease inhibitor.npj drug discovery · 2025Article
94 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The oral protease inhibitor nirmatrelvir is of key importance for prevention of severe coronavirus disease 2019 (COVID-19). To facilitate resistance monitoring, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir in cell culture. Resistant variants harbored combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetics revealed that E166V and L50F + E166V conferred high resistance in infectious culture, replicon, and Mpro systems. While L50F, E166V, and L50F + E166V decreased replication and Mpro activity, L50F and L50F + E166V variants had high fitness in the infectious system. Naturally occurring L50F compensated for fitness cost of E166V and promoted viral escape. Molecular dynamics simulations revealed that E166V and L50F + E166V weakened nirmatrelvir-Mpro binding. Polymerase inhibitor remdesivir and monoclonal antibody bebtelovimab retained activity against nirmatrelvir-resistant variants, and combination with nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatments with efficacy against SARS-CoV-2 and emerging sarbecoviruses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.