The Chemical Synthesis of DNA and RNA Oligonucleotides for Drug Development and Therapeutic Applications

Abstract

Synthetic DNA and RNA sequences have been and are still broadly used in the development of a plethora of therapeutic, diagnostic and genomic applications. This report provides updates on improvements made to the phosphoramidite approach to solid-phase synthesis of native and modified nucleic acid sequences with the objective of increasing the quality of those synthetic nucleic acid sequences in terms of purity to ensure the safety and efficacy of potential nucleic acid-based drugs for the treatment of human diseases. The use of deoxyribonucleoside H-phosphonate monomers, as an alternative to phosphoramidite monomers, is highlighted to demonstrate the versatility of the H-phosphonate approach to the solid-phase synthesis of modified oligonucleotides. Furthermore, the solid-phase synthesis of RNA sequences is substantially revised with a particular emphasis on the selection of 2′-hydroxyl protecting groups for ribonucleosides and their phosphoramidite derivatives. Updates have been made to better address issues associated with the manufacture of RNA sequences, particularly in the context of drug discovery and cellular/tissue delivery for potential therapeutic applications.