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- Title
Development of bis-locked nucleic acid (bisLNA) oligonucleotides for efficient invasion of supercoiled duplex DNA.
- Authors
Moreno, Pedro M D; Geny, Sylvain; Pabon, Y Vladimir; Bergquist, Helen; Zaghloul, Eman M; Rocha, Cristina S J; Oprea, Iulian I; Bestas, Burcu; Andaloussi, Samir El; Jørgensen, Per T; Pedersen, Erik B; Lundin, Karin E; Zain, Rula; Wengel, Jesper; Smith, C I Edvard
- Abstract
In spite of the many developments in synthetic oligonucleotide (ON) chemistry and design, invasion into double-stranded DNA (DSI) under physiological salt and pH conditions remains a challenge. In this work, we provide a new ON tool based on locked nucleic acids (LNAs), designed for strand invasion into duplex DNA (DSI). We thus report on the development of a clamp type of LNA ON-bisLNA-with capacity to bind and invade into supercoiled double-stranded DNA. The bisLNA links a triplex-forming, Hoogsteen-binding, targeting arm with a strand-invading Watson-Crick binding arm. Optimization was carried out by varying the number and location of LNA nucleotides and the length of the triplex-forming versus strand-invading arms. Single-strand regions in target duplex DNA were mapped using chemical probing. By combining design and increase in LNA content, it was possible to achieve a 100-fold increase in potency with 30% DSI at 450 nM using a bisLNA to plasmid ratio of only 21:1. Although this first conceptual report does not address the utility of bisLNA for the targeting of DNA in a chromosomal context, it shows bisLNA as a promising candidate for interfering also with cellular genes.
- Publication
Nucleic acids research, 2013, Vol 41, Issue 5, p3257
- ISSN
1362-4962
- Publication type
Journal Article
- DOI
10.1093/nar/gkt007