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7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy
Antisense oligonucleotides are small pieces of modified DNA or RNA, which offer therapeutic potential for many diseases. We report on the synthesis of 7′,5′-α-bc-DNA phosphoramidite building blocks, bearing the A, G, T and (Me)C nucleobases. Solid-phase synthesis was performed to construct five olig...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643641/ https://www.ncbi.nlm.nih.gov/pubmed/34850138 http://dx.doi.org/10.1093/nar/gkab1097 |
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author | Evéquoz, Damien Verhaart, Ingrid E C van de Vijver, Davy Renner, Wolfgang Aartsma-Rus, Annemieke Leumann, Christian J |
author_facet | Evéquoz, Damien Verhaart, Ingrid E C van de Vijver, Davy Renner, Wolfgang Aartsma-Rus, Annemieke Leumann, Christian J |
author_sort | Evéquoz, Damien |
collection | PubMed |
description | Antisense oligonucleotides are small pieces of modified DNA or RNA, which offer therapeutic potential for many diseases. We report on the synthesis of 7′,5′-α-bc-DNA phosphoramidite building blocks, bearing the A, G, T and (Me)C nucleobases. Solid-phase synthesis was performed to construct five oligodeoxyribonucleotides containing modified thymidine residues, as well as five fully modified oligonucleotides. Incorporations of the modification inside natural duplexes resulted in strong destabilizing effects. However, fully modified strands formed very stable duplexes with parallel RNA complements. In its own series, 7′,5′-α-bc-DNA formed duplexes with a surprising high thermal stability. CD spectroscopy and extensive molecular modeling indicated the adoption by the homo-duplex of a ladder-like structure, while hetero-duplexes with DNA or RNA still form helical structure. The biological properties of this new modification were investigated in animal models for Duchenne muscular dystrophy and spinal muscular atrophy, where exon splicing modulation can restore production of functional proteins. It was found that the 7′,5′-α-bc-DNA scaffold confers a high biostability and a good exon splicing modulation activity in vitro and in vivo. |
format | Online Article Text |
id | pubmed-8643641 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86436412021-12-06 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy Evéquoz, Damien Verhaart, Ingrid E C van de Vijver, Davy Renner, Wolfgang Aartsma-Rus, Annemieke Leumann, Christian J Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry Antisense oligonucleotides are small pieces of modified DNA or RNA, which offer therapeutic potential for many diseases. We report on the synthesis of 7′,5′-α-bc-DNA phosphoramidite building blocks, bearing the A, G, T and (Me)C nucleobases. Solid-phase synthesis was performed to construct five oligodeoxyribonucleotides containing modified thymidine residues, as well as five fully modified oligonucleotides. Incorporations of the modification inside natural duplexes resulted in strong destabilizing effects. However, fully modified strands formed very stable duplexes with parallel RNA complements. In its own series, 7′,5′-α-bc-DNA formed duplexes with a surprising high thermal stability. CD spectroscopy and extensive molecular modeling indicated the adoption by the homo-duplex of a ladder-like structure, while hetero-duplexes with DNA or RNA still form helical structure. The biological properties of this new modification were investigated in animal models for Duchenne muscular dystrophy and spinal muscular atrophy, where exon splicing modulation can restore production of functional proteins. It was found that the 7′,5′-α-bc-DNA scaffold confers a high biostability and a good exon splicing modulation activity in vitro and in vivo. Oxford University Press 2021-11-26 /pmc/articles/PMC8643641/ /pubmed/34850138 http://dx.doi.org/10.1093/nar/gkab1097 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Evéquoz, Damien Verhaart, Ingrid E C van de Vijver, Davy Renner, Wolfgang Aartsma-Rus, Annemieke Leumann, Christian J 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title | 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title_full | 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title_fullStr | 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title_full_unstemmed | 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title_short | 7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy |
title_sort | 7′,5′-alpha-bicyclo-dna: new chemistry for oligonucleotide exon splicing modulation therapy |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643641/ https://www.ncbi.nlm.nih.gov/pubmed/34850138 http://dx.doi.org/10.1093/nar/gkab1097 |
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