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In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance

Journal Article · · Science Advances
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  1. Pfizer Worldwide Research, Pearl River, NY (United States)
  2. Pfizer Worldwide Research, Groton, CT (United States)
  3. Pfizer Worldwide Research, Cambridge MA (United States)
  4. Pfizer Worldwide Research, Pearl River, NY (United States); Texas Biomedical Research Institute, San Antonio, TX (United States)
  5. Pfizer Worldwide Research, La Jolla, CA (United States); Genesis Therapeutics, San Diego, CA (United States)
  6. Pfizer Worldwide Research, La Jolla, CA (United States)
  7. Pfizer Worldwide Research, Groton, CT (United States); Roche Pharmaceuticals, Basel (Switzerland)
+ Show Author Affiliations
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus Mpro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six Mpro mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and Mpro activity. SARS-CoV-2 surveillance revealed that in vitro resistance–associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19–related hospitalization or death.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2470037
Journal Information:
Science Advances, Journal Name: Science Advances Journal Issue: 30 Vol. 10; ISSN 2375-2548
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English

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