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*

*Kontaktforfatter for dette arbejde

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftChemistry - A European Journal
Vol/bind27
Udgave nummer4
Sider (fra-til)1416-1422
ISSN0947-6539
DOI
StatusUdgivet - 18. jan. 2021

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