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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Published inPLoS pathogens Vol. 19; no. 3; p. e1011231
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 27.03.2023
Public Library of Science (PLoS)
Subjects
Amino acids
Analysis
Antiviral activity
Antiviral Agents - metabolism
Antiviral drugs
Binding Sites
Biology and life sciences
Cloning
Coronaviruses
COVID-19
COVID-19 Drug Treatment
Drug resistance
Epidemics
FDA approval
Flexibility
Genomes
Genomics
Health aspects
Humans
Infection
Japan
Mathematical models
Medical research
Medicine and health sciences
Medicine, Experimental
Molecular dynamics
Mutagenesis
Mutants
Mutation
Physical Sciences
Prevention
Ribonucleic acid
RNA
RNA polymerase
RNA, Viral
SARS-CoV-2 - metabolism
Severe acute respiratory syndrome coronavirus 2
Vibration
Viral diseases
Virus diseases
Viruses
Japan
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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.
AbstractList 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.
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.
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. Considering the emerging Omicron strain, quick characterization of SARS-CoV-2 mutations is important. However, owing to the difficulties in genetically modifying SARS-CoV-2, limited groups have produced multiple mutant viruses. Our cutting-edge reverse genetics technique enabled construction of eight reporter-carrying SARS-CoV-2 with 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. We developed a mathematical model taking into account sequential changes and identified antiviral effects against mutant viruses with differing propagation capacities and lethal effects on cells. In addition to identifying the positions of mutations, we analyzed the structural changes in SARS-CoV-2 NSP12 by computer simulation to understand the mechanism of resistance. This multidisciplinary approach promotes the evaluation of future resistance mutations.
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.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.
Audience Academic
Author Shimamura, Teppei
Asakura, Hiroyuki
Sato, Kei
Koseki, Jun
Fukuhara, Takasuke
Jeong, Yong Dam
Iwanami, Shoya
Iwami, Shingo
Torii, Shiho
Nagashima, Mami
Kim, Kwang Su
Suzuki, Rigel
Ito, Jumpei
Sadamasu, Kenji
Yoshimura, Kazuhisa
Fujita, Yasuhisa
Matsuura, Yoshiharu
AuthorAffiliation 9 International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
13 Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan
18 AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
2 interdisciplinary Biology Laboratory (iBLab), Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan
6 Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
8 International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
15 NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
11 CREST, Japan Science and Technology Agency, Kawaguchi, Japan
16 Interdisciplinary Theoretical and Mathematical Sciences Program (iTHEMS), RIKEN, Saitama, Japan
1 Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
12 Center for Infectious Disease Education and Resea
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36972312$$D View this record in MEDLINE/PubMed
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Copyright 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.
COPYRIGHT 2023 Public Library of Science
2023 Torii et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2023 Torii et al 2023 Torii et al
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– notice: 2023 Torii et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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License 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.
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Current address: Insect-Virus Interactions Unit, Department of Virology, Institute Pasteur, Paris, France
Membership of The Genotype to Phenotype Japan (G2P-Japan) Consortium is provided in Supporting Information file [S1 Acknowledgement].
The authors have declared that no competing interests exist.
Current address: Department of Scientific computing, Pukyong National University, Busan, South Korea
ORCID 0000-0001-9091-8285
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Snippet 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...
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SubjectTerms Amino acids
Analysis
Antiviral activity
Antiviral Agents - metabolism
Antiviral drugs
Binding Sites
Biology and life sciences
Cloning
Coronaviruses
COVID-19
COVID-19 Drug Treatment
Drug resistance
Epidemics
FDA approval
Flexibility
Genomes
Genomics
Health aspects
Humans
Infection
Japan
Mathematical models
Medical research
Medicine and health sciences
Medicine, Experimental
Molecular dynamics
Mutagenesis
Mutants
Mutation
Physical Sciences
Prevention
Ribonucleic acid
RNA
RNA polymerase
RNA, Viral
SARS-CoV-2 - metabolism
Severe acute respiratory syndrome coronavirus 2
Vibration
Viral diseases
Virus diseases
Viruses
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Title Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir
URI https://www.ncbi.nlm.nih.gov/pubmed/36972312
https://www.proquest.com/docview/2802052721
https://www.proquest.com/docview/2791709477
https://pubmed.ncbi.nlm.nih.gov/PMC10089321
https://doaj.org/article/d357fa629fa24023ac92f08664dbc0ff
http://dx.doi.org/10.1371/journal.ppat.1011231
Volume 19
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