The Medicinal Chemistry of Oligonucleotides
This review will focus on the properties that an oligonucleotide drug must have, the many modifications available to the medicinal chemist to engineer those properties into the oligonucleotide, and finally on motifs that have been utilized in oligonucleotide drugs and drug candidates. No attempt has been made to be exhaustively complete in the coverage. We have instead highlighted properties of modifications, and strategies that we feel are likely to be successful in drug development, of value to the field, as well as those that add to the understanding of oligonucleotide medicinal chemistry. Much of the discussion centers around RNase H-based antisense therapeutics, since most of the efforts to optimize oligonucleotide drugs has focused on that application. However, the chemical modifications and principles apply equally to other classes of oligonucleotide drugs, including immunostimulatory motifs, aptamers, microRNA inhibitors, and duplex small interfering RNAs (siRNAs).