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Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir

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 var...

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Autores principales: Torii, Shiho, Kim, Kwang Su, Koseki, Jun, Suzuki, Rigel, Iwanami, Shoya, Fujita, Yasuhisa, Jeong, Yong Dam, Ito, Jumpei, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Sato, Kei, Matsuura, Yoshiharu, Shimamura, Teppei, Iwami, Shingo, Fukuhara, Takasuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089321/
https://www.ncbi.nlm.nih.gov/pubmed/36972312
http://dx.doi.org/10.1371/journal.ppat.1011231
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author Torii, Shiho
Kim, Kwang Su
Koseki, Jun
Suzuki, Rigel
Iwanami, Shoya
Fujita, Yasuhisa
Jeong, Yong Dam
Ito, Jumpei
Asakura, Hiroyuki
Nagashima, Mami
Sadamasu, Kenji
Yoshimura, Kazuhisa
Sato, Kei
Matsuura, Yoshiharu
Shimamura, Teppei
Iwami, Shingo
Fukuhara, Takasuke
author_facet Torii, Shiho
Kim, Kwang Su
Koseki, Jun
Suzuki, Rigel
Iwanami, Shoya
Fujita, Yasuhisa
Jeong, Yong Dam
Ito, Jumpei
Asakura, Hiroyuki
Nagashima, Mami
Sadamasu, Kenji
Yoshimura, Kazuhisa
Sato, Kei
Matsuura, Yoshiharu
Shimamura, Teppei
Iwami, Shingo
Fukuhara, Takasuke
author_sort Torii, Shiho
collection PubMed
description 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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spelling pubmed-100893212023-04-12 Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir Torii, Shiho Kim, Kwang Su Koseki, Jun Suzuki, Rigel Iwanami, Shoya Fujita, Yasuhisa Jeong, Yong Dam Ito, Jumpei Asakura, Hiroyuki Nagashima, Mami Sadamasu, Kenji Yoshimura, Kazuhisa Sato, Kei Matsuura, Yoshiharu Shimamura, Teppei Iwami, Shingo Fukuhara, Takasuke PLoS Pathog Research Article 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. Public Library of Science 2023-03-27 /pmc/articles/PMC10089321/ /pubmed/36972312 http://dx.doi.org/10.1371/journal.ppat.1011231 Text en © 2023 Torii et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Torii, Shiho
Kim, Kwang Su
Koseki, Jun
Suzuki, Rigel
Iwanami, Shoya
Fujita, Yasuhisa
Jeong, Yong Dam
Ito, Jumpei
Asakura, Hiroyuki
Nagashima, Mami
Sadamasu, Kenji
Yoshimura, Kazuhisa
Sato, Kei
Matsuura, Yoshiharu
Shimamura, Teppei
Iwami, Shingo
Fukuhara, Takasuke
Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title_full Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title_fullStr Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title_full_unstemmed Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title_short Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
title_sort increased flexibility of the sars-cov-2 rna-binding site causes resistance to remdesivir
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089321/
https://www.ncbi.nlm.nih.gov/pubmed/36972312
http://dx.doi.org/10.1371/journal.ppat.1011231
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