Nirmatrelvir Resistant SARS-CoV-2 Variants with High Fitness in Vitro

• DOI: 10.1101/2022.06.06.494921
• Publication Date: 2022-06-08T02:45:10Z
• Authors: Yuyong Zhou; Karen Anbro Gamme...; Line Abildgaard R...; Long V. Pham; Ulrik Fahnøe; Alekxander Binderup; Carlos Rene Duart...; Anna Offersgaard; Carlota Fernandez...; Günther Herbert J...; Santseharay Ramirez; Jens Bukh; Judith Margarete ...
• Keywords: Coronavirus; Protease inhibitor (pharmacology)

Abstract The oral protease inhibitor nirmatrelvir is expected to play a pivotal role for prevention of severe cases coronavirus disease 2019 (COVID-19). To facilitate monitoring potentially emerging resistance, we studied acute respiratory syndrome 2 (SARS-CoV-2) escape from nirmatrelvir. Resistant variants selected in cell culture harbored different combinations substitutions the SARS-CoV-2 main (Mpro). Reverse genetic studies homologous infectious system revealed up 80-fold resistance conferred by combination L50F and E166V. had high fitness increasing likelihood occurrence spread resistance. Molecular dynamics simulations that E166V L50F+E166V weakened nirmatrelvir-Mpro binding. polymerase remdesivir retained activity against resistant enhanced treatment efficacy compared individual compounds. These findings have implications ensuring programs with coronaviruses.