Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system-Reference-Cited by-同舟云学术

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

Published:2022-12-21 Issue:51 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Zhou Yuyong¹²^ORCID,Gammeltoft Karen Anbro¹²^ORCID,Ryberg Line Abildgaard¹²^ORCID,Pham Long V.¹²,Tjørnelund Helena Damtoft³^ORCID,Binderup Alekxander¹²^ORCID,Duarte Hernandez Carlos Rene¹²,Fernandez-Antunez Carlota¹²,Offersgaard Anna¹²^ORCID,Fahnøe Ulrik¹²^ORCID,Peters Günther Herbert Johannes³^ORCID,Ramirez Santseharay¹²^ORCID,Bukh Jens¹²^ORCID,Gottwein Judith Margarete¹²^ORCID

Affiliation:

1. Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital–Hvidovre, 2650 Hvidovre, Denmark.

2. CO-HEP, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

3. Department of Chemistry, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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