Derivative Synthesis toward Enhancement of the Biophysical Properties of 2′,4′-Bridged Nucleic Acids

Abstract

Over the past few decades, a number of modified oligonucleotides have been synthesized and evaluated their biophysical properties. Modified oligonucleotides having high enzymatic stability, high duplex-forming ability toward single-stranded RNA (ssRNA), high sequence specificity, and good pharmacokinetic profiles, are highly desirable for therapeutic applications. We previously demonstrated that oligonucleotides modified with 2′-O,4′-C-methylene bridged nucleic acid/locked nucleic acid (2′,4′-BNA/LNA) have extremely high duplex-forming ability toward ssRNA. In recent years, we have been focusing on developing further strengthened bridged nucleic acids, e.g. 2′,4′-BNA/LNA analogues showing high enzymatic stability, high sequence specificity, high efficacy, and low toxicity. We herein report several promising bridged nucleic acids developed recently for therapeutic applications, especially in antisense and splice-switching oligonucleotides.