Liquid-phase synthesis of oligonucleotides

Abstract

This review will summarize recent progress of liquid-phase oligonucleotide synthesis and also briefly introduce the challenge to develop a process that applies our original liquid-phase synthesis technology for practical use. Recent progress in various types of oligonucleotide therapeutics, such as antisense, aptamer, siRNA and miRNA, has led to growing demand for economical and/or large scale production. Conventionally-known solid-phase synthesis which has been only a method of choice over the past few decades rapidly supplies oligonucleotides in high quality but in a limited quantity. Major issues of solid-phase synthesis that need to be addressed are scale-up and manufacturing cost. The former is attributable to the dedicated synthesizer's capacity and the latter associate with heterogeneous reactions: use of expensive resins and excess amidite reagents. Liquid-phase approaches may overcome these limitations. Behind the progress of solid-phase synthesis, researchers have investigated unique liquid-phase approaches. Among them, several methods utilizing soluble supports instead of solid resins are combining the advantage of solid-phase synthesis and liquid-phase synthesis, and expected to have possibility of industry applicable methods.