Polyamine-functionalized 2'-amino-LNA in oligonucleotides: Facile synthesis of novel monomers and high affinity binding towards ssDNA and dsDNA.

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