Polyamine-Functionalized 2′-Amino-LNA in Oligonucleotides: Facile Synthesis of New Monomers and High-Affinity Binding towards ssDNA and dsDNA

Mathias B. Danielsen, Niels Johan Christensen, Per T. Jørgensen, Knud J. Jensen, Jesper Wengel, Chenguang Lou*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Attachment of cationic moieties to oligonucleotides (ONs) promises not only to increase the binding affinity of antisense ONs by reducing charge repulsion between the two negatively charged strands of a duplex, but also to augment their in vivo stability against nucleases. In this study, polyamine functionality was introduced into ONs by means of 2′-amino-LNA scaffolds. The resulting ONs exhibited efficient binding towards ssDNA, ssRNA and dsDNA targets, and the 2′-amino-LNA analogue carrying a triaminated linker showed the most pronounced duplex- and triplex-stabilizing effect. Molecular modelling revealed that favourable conformational and electrostatic effects led to salt-bridge formation between positively charged polyamine moieties and the Watson–Hoogsteen groove of the dsDNA targets, resulting in the observed triplex stabilization. All the investigated monomers showed increased resistance against 3′-nucleolytic digestion relative to the non-functionalized controls.

Original languageEnglish
JournalChemistry - A European Journal
Volume27
Issue number4
Pages (from-to)1416-1422
ISSN0947-6539
DOIs
Publication statusPublished - 18. Jan 2021

Keywords

  • amines
  • click chemistry
  • DNA
  • molecular modelling
  • oligonucleotides

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