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

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 harbor...

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Bibliographic Details
Published in:	Science advances Vol. 8; no. 51; p. eadd7197
Main Authors:	Zhou, Yuyong, Gammeltoft, Karen Anbro, Ryberg, Line Abildgaard, Pham, Long V, Tjørnelund, Helena Damtoft, Binderup, Alekxander, Duarte Hernandez, Carlos Rene, Fernandez-Antunez, Carlota, Offersgaard, Anna, Fahnøe, Ulrik, Peters, Günther Herbert Johannes, Ramirez, Santseharay, Bukh, Jens, Gottwein, Judith Margarete
Format:	Journal Article
Language:	English
Published:	United States American Association for the Advancement of Science 21-12-2022
Subjects:	Biomedicine and Life Sciences Cell Biology Cell Culture Techniques Communicable Diseases Coronavirus COVID-19 Genetics Humans Lactams Nitriles SARS-CoV-2 - genetics SciAdv r-articles
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	2375-2548 2375-2548
DOI:	10.1126/sciadv.add7197