Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA-Gapmer Approach.

Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA-Gapmer Approach.
Chembiochem. 2020 Jul 13;:
Authors: Wojtyniak M, Schmidtgall B, Kirsch P, Ducho C
Abstract
Oligonucleotides (ON) are promising therapeutic candidates, for instance by blocking endogenous mRNA (antisense mechanism). However, ON usually require structural modifications of the native nucleic acid backbone to ensure satisfying pharmacokinetic properties. One such strategy to design novel antisense oligonucleotides is the replacement of native phosphate diester units by positively charged artificial linkages, thus leading to (partially) zwitterionic backbone structures. Herein, we report a gapmer architecture comprised of one zwitterionic central segment ('gap') containing nucleosyl amino acid (NAA)-modifications and two outer segments of locked nucleic acid (LNA). This NAA/LNA-gapmer approach furnished a partially zwitterionic ON with optimised properties: (i) the formation of stable ON-RNA duplexes with base-pairing fidelity and superior target selectivity at 37 °C; and (ii) excellent stability in complex biological media. Overall, the NAA/LNA-gapmer approach is thus established as a strategy to design partially zwitterionic ON for the future development of novel antisense agents.
PMID: 32662164 [PubMed - as supplied by publisher]

Source: Chembiochem - July 12, 2020 Category: Biochemistry Authors: Wojtyniak M, Schmidtgall B, Kirsch P, Ducho C Tags: Chembiochem Source Type: research