CHAPTER 3: The Medicinal Chemistry of RNase H-activating Antisense Oligonucleotides

This review focuses on the properties that an RNase H-activating antisense oligonucleotide (ASO) drug must have to function effectively in animals, as well as on medicinal chemistry strategies to achieve these properties. The biochemistry and structural requirements for activating RNase H are briefly summarized, as well as chemical modifications that can effect activation of RNase H when an ASO is bound to target RNA. The key modifications available to the medicinal chemist to engineer desired properties of the ASO are briefly reviewed, as are ASO design strategies to achieve optimal activity in animal systems. Lastly, the interactions of ASOs with proteins and strategies to control these interactions to improve the profile of ASOs are discussed.