7',5'-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
02 12 2021
02 12 2021
Historique:
accepted:
25
10
2021
revised:
12
10
2021
received:
11
12
2020
pubmed:
2
12
2021
medline:
11
1
2022
entrez:
1
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34850138
pii: 6442724
doi: 10.1093/nar/gkab1097
pmc: PMC8643641
doi:
Substances chimiques
Oligonucleotides
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12089-12105Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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