Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides.

Mathias B Danielsen,Jesper Wengel

doi:10.3762/bjoc.17.125

Abstract

Antisense oligonucleotides (ASOs) have the ability of binding to endogenous nucleic acid targets, thereby inhibiting the gene expression. Although ASOs have great potential in the treatment of many diseases, the search for favorable toxicity profiles and distribution has been challenging and consequently impeded the widespread use of ASOs as conventional medicine. One strategy that has been employed to optimize the delivery profile of ASOs, is the functionalization of ASOs with cationic amine groups, either by direct conjugation onto the sugar, nucleobase or internucleotide linkage. The introduction of these positively charged groups has improved properties like nuclease resistance, increased binding to the nucleic acid target and improved cell uptake for oligonucleotides (ONs) and ASOs. The modifications highlighted in this review are some of the most prevalent cationic amine groups which have been attached as single modifications onto ONs/ASOs. The review has been separated into three sections, nucleobase, sugar and backbone modifications, highlighting what impact the cationic amine groups have on the ONs/ASOs physiochemical and biological properties. Finally, a concluding section has been added, summarizing the important knowledge from the three chapters, and examining the future design for ASOs.

Highlights

Antisense oligonucleotides (ASOs) are single-stranded oligomers composed of typically 10–25 nucleotides linked by negatively charged phosphorus-based linkages
We focus on important monomeric cationic modifications for ASOs, including locked nucleic acid (LNA) monomers, and their synthesis
This includes the position of a modification as well as the chemical composition of the cationic group, and what scaffold the cationic group is to be attached to, i.e., is it a 2’-amino-LNA nucleotide or the common DNA/RNA nucleotides

Summary

Introduction

Antisense oligonucleotides (ASOs) are single-stranded (ss) oligomers composed of typically 10–25 nucleotides linked by negatively charged phosphorus-based linkages. Such modifications have been achieved either by direct conjugation to the nucleobase, the sugar or the backbone of nucleotide monomers of such ASOs. In addition, a table design showing which modification has duplex stabilizing properties, as well as improved nuclease resistance and cell activity, has been chosen for optimal visual presentation.

Results

Conclusion