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An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides

Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. W...

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Autores principales: Baker, Ysobel R., Thorpe, Cameron, Chen, Jinfeng, Poller, Laura M., Cox, Lina, Kumar, Pawan, Lim, Wooi F., Lie, Lillian, McClorey, Graham, Epple, Sven, Singleton, Daniel, McDonough, Michael A., Hardwick, Jack S., Christensen, Kirsten E., Wood, Matthew J. A., Hall, James P., El-Sagheer, Afaf H., Brown, Tom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276774/
https://www.ncbi.nlm.nih.gov/pubmed/35821218
http://dx.doi.org/10.1038/s41467-022-31636-2
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author Baker, Ysobel R.
Thorpe, Cameron
Chen, Jinfeng
Poller, Laura M.
Cox, Lina
Kumar, Pawan
Lim, Wooi F.
Lie, Lillian
McClorey, Graham
Epple, Sven
Singleton, Daniel
McDonough, Michael A.
Hardwick, Jack S.
Christensen, Kirsten E.
Wood, Matthew J. A.
Hall, James P.
El-Sagheer, Afaf H.
Brown, Tom
author_facet Baker, Ysobel R.
Thorpe, Cameron
Chen, Jinfeng
Poller, Laura M.
Cox, Lina
Kumar, Pawan
Lim, Wooi F.
Lie, Lillian
McClorey, Graham
Epple, Sven
Singleton, Daniel
McDonough, Michael A.
Hardwick, Jack S.
Christensen, Kirsten E.
Wood, Matthew J. A.
Hall, James P.
El-Sagheer, Afaf H.
Brown, Tom
author_sort Baker, Ysobel R.
collection PubMed
description Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.
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spelling pubmed-92767742022-07-14 An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides Baker, Ysobel R. Thorpe, Cameron Chen, Jinfeng Poller, Laura M. Cox, Lina Kumar, Pawan Lim, Wooi F. Lie, Lillian McClorey, Graham Epple, Sven Singleton, Daniel McDonough, Michael A. Hardwick, Jack S. Christensen, Kirsten E. Wood, Matthew J. A. Hall, James P. El-Sagheer, Afaf H. Brown, Tom Nat Commun Article Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology. Nature Publishing Group UK 2022-07-12 /pmc/articles/PMC9276774/ /pubmed/35821218 http://dx.doi.org/10.1038/s41467-022-31636-2 Text en © Crown 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Baker, Ysobel R.
Thorpe, Cameron
Chen, Jinfeng
Poller, Laura M.
Cox, Lina
Kumar, Pawan
Lim, Wooi F.
Lie, Lillian
McClorey, Graham
Epple, Sven
Singleton, Daniel
McDonough, Michael A.
Hardwick, Jack S.
Christensen, Kirsten E.
Wood, Matthew J. A.
Hall, James P.
El-Sagheer, Afaf H.
Brown, Tom
An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title_full An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title_fullStr An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title_full_unstemmed An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title_short An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
title_sort lna-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276774/
https://www.ncbi.nlm.nih.gov/pubmed/35821218
http://dx.doi.org/10.1038/s41467-022-31636-2
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