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

• DOI: 10.1126/sciadv.add7197
• Publication Date: 2022-12-21T18:58:26Z
• Authors: Yuyong Zhou; Karen Anbro Gamme...; Line Abildgaard R...; Long V. Pham; Helena Damtoft Tj...; Alekxander Binderup; Carlos Rene Duart...; Carlota Fernandez...; Anna Offersgaard; Ulrik Fahnøe; Günther Herbert J...; Santseharay Ramirez; Jens Bukh; Judith Margarete ...
• Keywords: Replicon; Coronavirus

The oral protease inhibitor nirmatrelvir is of key importance for prevention severe coronavirus disease 2019 (COVID-19). To facilitate resistance monitoring, we studied acute respiratory syndrome 2 (SARS-CoV-2) escape from in cell culture. Resistant variants harbored combinations substitutions the SARS-CoV-2 main (Mpro). Reverse genetics revealed that E166V and L50F + conferred high infectious culture, replicon, Mpro systems. While L50F, E166V, decreased replication activity, had fitness system. Naturally occurring compensated cost promoted viral escape. Molecular dynamics simulations weakened nirmatrelvir-Mpro binding. Polymerase remdesivir monoclonal antibody bebtelovimab retained activity against nirmatrelvir-resistant variants, combination with enhanced treatment efficacy compared to individual compounds. These findings have implications monitoring ensuring treatments emerging sarbecoviruses.