Recent advances in the medicinal chemistry of antisense oligonucleotides
Uhlmann, E.
Current Opinion in Drug Discovery and Development 3(2): 203-213
2000
ISSN/ISBN: 1367-6733 PMID: 19649851 Document Number: 526038
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.