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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. / Zhou, Yuyong; Gammeltoft, Karen Anbro; Ryberg, Line Abildgaard; Pham, Long V.; Tjørnelund, Helena Damtoft; Binderup, Alekxander; Hernandez, Carlos Rene Duarte; Fernandez-Antunez, Carlota; Offersgaard, Anna; Fahnøe, Ulrik; Peters, Günther Herbert Johannes; Ramirez, Santseharay; Bukh, Jens; Gottwein, Judith Margarete.

In: Science Advances, Vol. 8, No. 51, eadd7197, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Zhou, Y, Gammeltoft, KA, Ryberg, LA, Pham, LV, Tjørnelund, HD, Binderup, A, Hernandez, CRD, Fernandez-Antunez, C, Offersgaard, A, Fahnøe, U, Peters, GHJ, Ramirez, S, Bukh, J & Gottwein, JM 2022, 'Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system', Science Advances, vol. 8, no. 51, eadd7197. https://doi.org/10.1126/sciadv.add7197

APA

Zhou, Y., Gammeltoft, K. A., Ryberg, L. A., Pham, L. V., Tjørnelund, H. D., Binderup, A., Hernandez, C. R. D., Fernandez-Antunez, C., Offersgaard, A., Fahnøe, U., Peters, G. H. J., Ramirez, S., Bukh, J., & Gottwein, J. M. (2022). Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. Science Advances, 8(51), [eadd7197]. https://doi.org/10.1126/sciadv.add7197

Vancouver

Zhou Y, Gammeltoft KA, Ryberg LA, Pham LV, Tjørnelund HD, Binderup A et al. Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. Science Advances. 2022;8(51). eadd7197. https://doi.org/10.1126/sciadv.add7197

Author

Zhou, Yuyong ; Gammeltoft, Karen Anbro ; Ryberg, Line Abildgaard ; Pham, Long V. ; Tjørnelund, Helena Damtoft ; Binderup, Alekxander ; Hernandez, Carlos Rene Duarte ; Fernandez-Antunez, Carlota ; Offersgaard, Anna ; Fahnøe, Ulrik ; Peters, Günther Herbert Johannes ; Ramirez, Santseharay ; Bukh, Jens ; Gottwein, Judith Margarete. / Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. In: Science Advances. 2022 ; Vol. 8, No. 51.

Bibtex

@article{efb9e20d0cb0403eb81a5a86f2d1283e,
title = "Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system",
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.",
author = "Yuyong Zhou and Gammeltoft, {Karen Anbro} and Ryberg, {Line Abildgaard} and Pham, {Long V.} and Tj{\o}rnelund, {Helena Damtoft} and Alekxander Binderup and Hernandez, {Carlos Rene Duarte} and Carlota Fernandez-Antunez and Anna Offersgaard and Ulrik Fahn{\o}e and Peters, {G{\"u}nther Herbert Johannes} and Santseharay Ramirez and Jens Bukh and Gottwein, {Judith Margarete}",
note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",
year = "2022",
doi = "10.1126/sciadv.add7197",
language = "English",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "51",

}

RIS

TY - JOUR

T1 - Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system

AU - Zhou, Yuyong

AU - Gammeltoft, Karen Anbro

AU - Ryberg, Line Abildgaard

AU - Pham, Long V.

AU - Tjørnelund, Helena Damtoft

AU - Binderup, Alekxander

AU - Hernandez, Carlos Rene Duarte

AU - Fernandez-Antunez, Carlota

AU - Offersgaard, Anna

AU - Fahnøe, Ulrik

AU - Peters, Günther Herbert Johannes

AU - Ramirez, Santseharay

AU - Bukh, Jens

AU - Gottwein, Judith Margarete

N1 - Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1126/sciadv.add7197

DO - 10.1126/sciadv.add7197

M3 - Journal article

C2 - 36542720

AN - SCOPUS:85144598166

VL - 8

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 51

M1 - eadd7197

ER -

ID: 333620100