Oligonucleotide Conjugates: Rationale, Synthesis, and Applications

Abstract

Synthetic oligonucleotides can cause specific inhibition of gene expression by a variety of mechanisms (e.g., antigene, antisense, siRNA). Such oligonucleotides can also cause catalytic cleavage of the target sequence (e.g., ribozyme, DNAzyme) and selectively bind to the target molecules (e.g., aptamers). However, oligonucleotides possess unfavorable pharmacokinetic and pharmacodynamic properties, like extremely short plasma half-life due to the degradation by nucleases, low cellular uptake, and poor target specificity. These unfavorable properties can be improved by either incorporating structural modifications in oligonucleotide or by conjugating (covalently linking) molecules with relevant biological properties (e.g., peptides and proteins, carbohydrates, antibodies, enzymes, polymers, drugs, fluorophores) to oligonucleotide. The conjugate design usually aims to improve the poor pharmacokinetic and pharmacodynamic properties of the unmodified oligonucleotide and, in some cases, to impart new properties to the oligonucleotide. Over the years, a very large number of diverse oligonucleotide conjugates have been developed and evaluated for diagnostic, therapeutic, and nanotechnology-based applications. The aim of this chapter is to describe the underlying reasons and challenges in oligonucleotide conjugate design, provide an overview of chemical approaches available for their synthesis, and highlight some of their recent applications.