Challenges and Opportunities for Oligonucleotide-Based Therapeutics by Antisense and RNA Interference Mechanisms

Abstract

Oligonucleotide-based therapeutics may be one of the most promising approaches for the treatment of diseases. Although significant progress has been made in developing these agents as drugs, several hurdles remain to be overcome. One of the most promising approaches to overcome these difficulties is the preparation of modified oligonucleotides designed to increase cellular uptake and/or increase stability to nucleases. Herein, we report the developments done by our group in the synthesis of modified oligonucleotides directed to the generation of active compounds for gene inhibition. Specifically we will report the synthesis of novel nuclease-resistant oligonucleotides such as North bicyclo[3.1.0]hexane pseudosugars or N-coupled dinucleotide units. Also, the design of several siRNA conjugates carrying cell-penetrating peptides, lipids, intercalating agents, and carbohydrates will be described. Some of these novel derivatives show clear improvements in their biological and inhibitory properties.