Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA‐Gapmer Approach. (28th August 2020)

• Record Type: Journal Article
• Authors: Wojtyniak, Melissa; Schmidtgall, Boris; Kirsch, Philine; Ducho, Christian
• Is Part Of: Chembiochem. Volume 21:Number 22(2020)
• Page Start: 3234
• Page End: 3243
• Publication Date: 2020-08-28
• Subjects: antisense -- backbone modification -- gapmers -- oligonucleotides -- zwitterions; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202000450
• Languages: English
• ISSNs: 1439-4227

Abstract

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 to replace 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. Abstract : Mind the gap ! One approach towards backbone‐modified oligonucleotides is the introduction of (partially) zwitterionic structural motifs. In this work, we report a "gapmer" architecture comprising a zwitterionic central "gap" (with cationic NAA linkages) and two outer segments of locked nucleic acid (LNA). This NAA/LNA‐gapmer approach furnished a partially zwitterionic oligonucleotide with promising properties for potential biomedical applications.