Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Dokumenter

  • Fulltext

    Forlagets udgivne version, 1,51 MB, PDF-dokument

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.

OriginalsprogEngelsk
Artikelnummereadd7197
TidsskriftScience Advances
Vol/bind8
Udgave nummer51
ISSN2375-2548
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank B. Ørskov Lindhardt (Copenhagen University Hospital-Hvidovre) and C. Menne Bonefeld (University of Copenhagen) for support and L. Mikkelsen and A.-L. Sørensen (Copenhagen University Hospital-Hvidovre) for laboratory assistance. We thank J. Dubuisson and S. Belouzard for providing VeroE6 cells. Funding: This work was supported by PhD stipends from the Candys Foundation (K.A.G., A.O., C.F.-A., J.B., and J.M.G.) and the China Scholarship Council (Y.Z. and J.M.G.) and by grants from the Amager and Hvidovre Hospital Research Foundation (C.R.D.H. and J.M.G.), the Danish Agency for Science and Higher Education (S.R., J.B., and J.M.G.), the Independent Research Fund Denmark (J.B.), the Innovation Fund Denmark (J.M.G.), the Novo Nordisk Foundation including a Distinguished Investigator Grant (J.B.), Mauritzen la Fontaine Fonden (J.B.), Mauritzen La Fontaine Familiefond (J.B.), the Region H Foundation (J.B. and J.M.G.), the Toyota Foundation (J.M.G.), and the Weimann Foundation (U.F.).

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.

ID: 333620100