Antisense drug discovery and development technology considered in a pharmacological context

When coined, the term antisense included oligonucleotides of any structure, with any chemical modification and designed to work through any post-RNA hybridization mechanism. However, in practice the term antisense has been used to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to RNAs while the term siRNA has come to mean double stranded oligonucleotides designed to activate Ago2. However, the two approaches share many common features. The medicinal chemistry developed for ASOs greatly facilitated the development of siRNA technology and remains the chemical basis for both approaches. Many of challenges faced and solutions achieved share many common features. In fact, because ss ASOs can be designed to activate Ago2, the two approaches intersect at this remarkably important protein. There are also meaningful differences. The pharmacokinetic properties are quite different and thus potential routes of delivery differ. ASOs may be designed to use a variety of post-RNA binding mechanisms while siRNAs depend solely on the robust activity of Ago2. However, siRNAs and ASOs are both used for therapeutic purposes and both must be and can be understood in a pharmacological context. Thus, the goals of this review are to put ASOs in pharmacological context and compare their behavior as pharmacological agents to the those of siRNAs.

Automated summary

This article discusses the application and comparison of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) in a pharmacological context. While the two approaches share common features, they also have significant differences in terms of chemical modifications, mechanisms of action, and pharmacokinetic properties.