Mixed-Backbone Oligonucleotides for Therapeutics: The Way of the Future

Abstract

Conventional oligonucleotides, such as DNA and RNA, are extensively modified for therapeutic applications. The mixed-backbone oligonucleotides (MBOs) that are generated by combining different classes have superior properties such as enhanced mRNA binding affinity, improved distribution, and reduced toxicity. Oligonucleotides act on mRNA in different ways, such as RNase H-mediated decay, RNA interference, and splice switching, and require specific modification patterns in each case. Hence, understanding the scope of different modifications and their synthetic compatibility is fundamental to the blueprint of future MBOs. In this Perspective, the important design considerations of mixed-backbone oligonucleotides have been presented for the most common types of mRNA-targeting oligonucleotides. The synthetic principles employed for the generation of chimeric MBOs using different phosphorus chemistries and execution modes (manual/automated) have also been discussed. Finally, the evolution of MBOs in clinical studies has been presented with exemplification of FDA-approved ONs.