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Evéquoz D, Verhaart IEC, van de Vijver D, et al. 7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy. Nucleic Acids Res. 2021;49(21):12089-12105doi: 10.1093/nar/gkab1097.
Evéquoz, D., Verhaart, I. E. C., van de Vijver, D., Renner, W., Aartsma-Rus, A., & Leumann, C. J. (2021). 7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy. Nucleic acids research, 49(21), 12089-12105. https://doi.org/10.1093/nar/gkab1097
Evéquoz, Damien, et al. "7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy." Nucleic acids research vol. 49,21 (2021): 12089-12105. doi: https://doi.org/10.1093/nar/gkab1097
Evéquoz D, Verhaart IEC, van de Vijver D, Renner W, Aartsma-Rus A, Leumann CJ. 7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy. Nucleic Acids Res. 2021 Dec 02;49(21):12089-12105. doi: 10.1093/nar/gkab1097. PMID: 34850138; PMCID: PMC8643641.
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Nucleic Acids Res. 2021 Dec 02;49(21):12089-12105. doi: 10.1093/nar/gkab1097.

7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy.

Nucleic acids research

Damien Evéquoz, Ingrid E C Verhaart, Davy van de Vijver, Wolfgang Renner, Annemieke Aartsma-Rus, Christian J Leumann

Affiliations

  1. Alpha Anomeric, 140 Bis, Rue de Rennes, 75006 Paris, France.
  2. Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
  3. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.

PMID: 34850138 PMCID: PMC8643641 DOI: 10.1093/nar/gkab1097

Abstract

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 MeC 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.

© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

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