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

Author:

Zhu Yuao1ORCID,Yurgelonis Irina1ORCID,Noell Stephen2ORCID,Yang Qingyi3,Guan Shunjie3,Li Zhenghui1,Hao Li1ORCID,Rothan Hussin1,Rai Devendra K.1,McMonagle Patricia1ORCID,Baniecki Mary Lynn3ORCID,Greasley Samantha E.4ORCID,Plotnikova Olga2,Lee Jonathan1,Nicki Jennifer A.2ORCID,Ferre RoseAnn4ORCID,Byrnes Laura J.2ORCID,Liu Wei4,Craig Timothy K.2ORCID,Steppan Claire M.2ORCID,Liberator Paul1ORCID,Soares Holly D.2ORCID,Allerton Charlotte M. N.3ORCID,Anderson Annaliesa S.1,Cardin Rhonda D.1ORCID

Affiliation:

1. Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA.

2. Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA.

3. Pfizer Worldwide Research, Development & Medical, Cambridge MA 02139, USA.

4. Pfizer Worldwide Research, Development & Medical, La Jolla, CA 92121, USA.

Abstract

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 M pro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M pro 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 M pro 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.

Publisher

American Association for the Advancement of Science (AAAS)

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