Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
Copyright: © 2023 Torii et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
PLoS pathogens - 19(2023), 3 vom: 23. März, Seite e1011231 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Torii, Shiho [VerfasserIn] |
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| Links: |
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| Themen: |
3QKI37EEHE |
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| Anmerkungen: |
Date Completed 13.04.2023 Date Revised 17.04.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.ppat.1011231 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354773585 |
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| 245 | 1 | 0 | |a Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir |
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| 520 | |a Copyright: © 2023 Torii et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Kim, Kwang Su |e verfasserin |4 aut | |
| 700 | 1 | |a Koseki, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Rigel |e verfasserin |4 aut | |
| 700 | 1 | |a Iwanami, Shoya |e verfasserin |4 aut | |
| 700 | 1 | |a Fujita, Yasuhisa |e verfasserin |4 aut | |
| 700 | 1 | |a Jeong, Yong Dam |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Jumpei |e verfasserin |4 aut | |
| 700 | 1 | |a Asakura, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Nagashima, Mami |e verfasserin |4 aut | |
| 700 | 1 | |a Sadamasu, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshimura, Kazuhisa |e verfasserin |4 aut | |
| 700 | 0 | |a Genotype to Phenotype Japan (G2P-Japan) Consortium |e verfasserin |4 aut | |
| 700 | 1 | |a Sato, Kei |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuura, Yoshiharu |e verfasserin |4 aut | |
| 700 | 1 | |a Shimamura, Teppei |e verfasserin |4 aut | |
| 700 | 1 | |a Iwami, Shingo |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuhara, Takasuke |e verfasserin |4 aut | |
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