Design and Synthesis of Protecting Groups for Pro-oligo Type Nucleic Acid-based Drugs

Abstract

Oligonucleotide-based therapeutics, such as antisense oligonucleotides and small interfering RNAs(siRNAs), are fast emerging as the next generation of chemotherapeutics. However, a major issue for oligonucleotide-based therapeutics involves effective intracellular delivery of the active molecules into the cells. Several methods such as lipid nanoparticle encapsulation and conjugation of functional molecules have been reported. As an alternative approach, the use of pro-oligonucleotides (pro-oligos) offers several advantages, including improved enzymatic stability, thereby avoiding the need for transfection reagents for the delivery of oligonucleotides into cells. We have developed several bio-labile protecting groups for the pro-oligos. This article describes the design and synthesis of bio-labile protecting groups and their application to pro-oligo type molecules for the development of oligonucleotide therapeutics.