Recent advances in the medicinal chemistry of antisense oligonucleotides

The therapeutic index of an antisense oligonucleotide is determined by its nucleotide sequence and the type of chemical modification. In the last decade, a great deal of effort has been devoted to the development of a second generation of novel antisense oligonucleotide analogs with improved properties compared to the uniformly phosphorothioate-modified oligonucleotides of the first generation. In this review, the advances in the medicinal chemistry of antisense oligonucleotides of the last 2 years will be discussed with emphasis on modifications of the phosphate backbone, heterocyclic bases, carbohydrate moiety and pendent groups for improved delivery. Understanding the basic rules by which a certain modification influences the mechanism of antisense action, binding affinity, metabolic stability, cellular uptake, toxicity and bioavailability of an oligonucleotide, will have a profound impact on the further development of antisense therapeutics.