Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression

A new type of drug molecule synthesized with a specific base sequence designed to interact with a target nucleic acid containing the complementary sequence are being developed. In the earliest and most developed example of this approach, oligodeoxynucleotides and their analogs have been applied as antisense inhibitors of gene expression to bring about translation arrest. This chapter discusses the use of antisense oligodeoxynucleotides as a therapeutic approach. Once this approach is recognized in principle, other examples can be seen to fit a pattern, such as the use of oligodeoxynucleotides to form a triple-strand helix with duplex DNA. However, with a different base triplet code to arrest transcription, the opening of duplex DNA is not considered facile enough to allow the access of an oligo to interact with one of the strands. The development of synthetic oligoribonucleotides as ribozymes is another example in which the information for the selectivity is encoded in the portions of the oligomer flanking the catalytic site. Another example is the use of oligodeoxynucleotides to bind to protein sites that recognize specific sequences of bases, thus, inhibiting polymerase action or bringing about transcription arrest by sequestering specific transcription cofactors. Thus, a new area of pharmacology is developing that is differentiated by the purposeful inclusion of information in the form of nucleic-acid bases in a putative oligonucleotide drug molecule.