In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 3 ( 2023-3-27), p. e1011231-
Abstract:
Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. We confirmed that all the mutant viruses didn’t gain the virus production efficiency without remdesivir treatment. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011231
DOI:
10.1371/journal.ppat.1011231.g001
DOI:
10.1371/journal.ppat.1011231.g002
DOI:
10.1371/journal.ppat.1011231.g003
DOI:
10.1371/journal.ppat.1011231.g004
DOI:
10.1371/journal.ppat.1011231.g005
DOI:
10.1371/journal.ppat.1011231.t001
DOI:
10.1371/journal.ppat.1011231.t002
DOI:
10.1371/journal.ppat.1011231.t003
DOI:
10.1371/journal.ppat.1011231.s001
DOI:
10.1371/journal.ppat.1011231.s002
DOI:
10.1371/journal.ppat.1011231.s003
DOI:
10.1371/journal.ppat.1011231.s004
DOI:
10.1371/journal.ppat.1011231.s005
DOI:
10.1371/journal.ppat.1011231.s006
DOI:
10.1371/journal.ppat.1011231.s007
DOI:
10.1371/journal.ppat.1011231.s008
DOI:
10.1371/journal.ppat.1011231.s009
DOI:
10.1371/journal.ppat.1011231.s010
DOI:
10.1371/journal.ppat.1011231.s011
DOI:
10.1371/journal.ppat.1011231.r001
DOI:
10.1371/journal.ppat.1011231.r002
DOI:
10.1371/journal.ppat.1011231.r003
DOI:
10.1371/journal.ppat.1011231.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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