Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system.
Sci Adv
; 8(51): eadd7197, 2022 12 21.
Article
in English
| MEDLINE | ID: covidwho-2193380
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Communicable Diseases
/
COVID-19
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Sci Adv
Year:
2022
Document Type:
Article
Affiliation country:
Sciadv.add7197
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