tetano
Editor, Senior Moderator
Sci Adv
. 2022 Dec 21;8(51):eadd7197.
doi: 10.1126/sciadv.add7197. Epub 2022 Dec 21.
Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system
Yuyong Zhou[SUP] 1 2 [/SUP], Karen Anbro Gammeltoft[SUP] 1 2 [/SUP], Line Abildgaard Ryberg[SUP] 1 2 [/SUP], Long V Pham[SUP] 1 2 [/SUP], Helena Damtoft Tjørnelund[SUP] 3 [/SUP], Alekxander Binderup[SUP] 1 2 [/SUP], Carlos Rene Duarte Hernandez[SUP] 1 2 [/SUP], Carlota Fernandez-Antunez[SUP] 1 2 [/SUP], Anna Offersgaard[SUP] 1 2 [/SUP], Ulrik Fahnøe[SUP] 1 2 [/SUP], Günther Herbert Johannes Peters[SUP] 3 [/SUP], Santseharay Ramirez[SUP] 1 2 [/SUP], Jens Bukh[SUP] 1 2 [/SUP], Judith Margarete Gottwein[SUP] 1 2 [/SUP]
Affiliations
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.
. 2022 Dec 21;8(51):eadd7197.
doi: 10.1126/sciadv.add7197. Epub 2022 Dec 21.
Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system
Yuyong Zhou[SUP] 1 2 [/SUP], Karen Anbro Gammeltoft[SUP] 1 2 [/SUP], Line Abildgaard Ryberg[SUP] 1 2 [/SUP], Long V Pham[SUP] 1 2 [/SUP], Helena Damtoft Tjørnelund[SUP] 3 [/SUP], Alekxander Binderup[SUP] 1 2 [/SUP], Carlos Rene Duarte Hernandez[SUP] 1 2 [/SUP], Carlota Fernandez-Antunez[SUP] 1 2 [/SUP], Anna Offersgaard[SUP] 1 2 [/SUP], Ulrik Fahnøe[SUP] 1 2 [/SUP], Günther Herbert Johannes Peters[SUP] 3 [/SUP], Santseharay Ramirez[SUP] 1 2 [/SUP], Jens Bukh[SUP] 1 2 [/SUP], Judith Margarete Gottwein[SUP] 1 2 [/SUP]
Affiliations
- PMID: 36542720
- DOI: 10.1126/sciadv.add7197
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.