Search

Your search keyword '"Günther Herbert Johannes Peters"' showing total 3 results
Start Over Author "Günther Herbert Johannes Peters"
3 results on '"Günther Herbert Johannes Peters"'

1. Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir

Author

Karen Anbro Gammeltoft, Yuyong Zhou, Line Abildgaard Ryberg, Long V. Pham, Alekxander Binderup, Carlos Rene Duarte Hernandez, Anna Offersgaard, Ulrik Fahnøe, Günther Herbert Johannes Peters, Santseharay Ramirez, Jens Bukh, and Judith Margarete Gottwein

Subjects
SARS-CoV-2, COVID-19, antiviral resistance, protease inhibitor, boceprevir, nirmatrelvir, Microbiology, QR1-502
Abstract

Nirmatrelvir, which targets the SARS-CoV-2 main protease (Mpro), is the first-in-line drug for prevention and treatment of severe COVID-19, and additional Mpro inhibitors are in development. However, the risk of resistance development threatens the future efficacy of such direct-acting antivirals. To gain knowledge on viral correlates of resistance to Mpro inhibitors, we selected resistant SARS-CoV-2 under treatment with the nirmatrelvir-related protease inhibitor boceprevir. SARS-CoV-2 selected during five escape experiments in VeroE6 cells showed cross-resistance to nirmatrelvir with up to 7.3-fold increased half-maximal effective concentration compared to original SARS-CoV-2, determined in concentration–response experiments. Sequence analysis revealed that escape viruses harbored Mpro substitutions L50F and A173V. For reverse genetic studies, these substitutions were introduced into a cell-culture-infectious SARS-CoV-2 clone. Infectivity titration and analysis of genetic stability of cell-culture-derived engineered SARS-CoV-2 mutants showed that L50F rescued the fitness cost conferred by A173V. In the concentration–response experiments, A173V was the main driver of resistance to boceprevir and nirmatrelvir. Structural analysis of Mpro suggested that A173V can cause resistance by making boceprevir and nirmatrelvir binding less favorable. This study contributes to a comprehensive overview of the resistance profile of the first-in-line COVID-19 treatment nirmatrelvir and can thus inform population monitoring and contribute to pandemic preparedness.

Published
2023
Full Text
View/download PDF

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

Author

Yuyong Zhou, Karen Anbro Gammeltoft, Line Abildgaard Ryberg, Long V. Pham, Ulrik Fahnøe, Alekxander Binderup, Carlos Rene Duarte Hernandez, Anna Offersgaard, Carlota Fernandez-Antunez, Günther Herbert Johannes Peters, Santseharay Ramirez, Jens Bukh, and Judith Margarete Gottwein

Abstract

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

Published
2022
Full Text
View/download PDF

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

Author

Yuyong Zhou, Karen Anbro Gammeltoft, Line Abildgaard Ryberg, Long V. Pham, Helena Damtoft Tjørnelund, Alekxander Binderup, Carlos Rene Duarte Hernandez, Carlota Fernandez-Antunez, Anna Offersgaard, Ulrik Fahnøe, Günther Herbert Johannes Peters, Santseharay Ramirez, Jens Bukh, and Judith Margarete Gottwein

Subjects
Multidisciplinary, Lactams, SARS-CoV-2, Nitriles, Cell Culture Techniques, Humans, COVID-19, Communicable Diseases
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.

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results