Although many issues remain to be resolved, recent progress suggests that
oligonucleotides may have therapeutic potential. The first therapeutic
oligonucleotide,
ISIS 2105, an
oligonucleotide designed to treat
genital warts, has completed Phase I clinical trials and is undergoing Phase II testing. Conceptually,
oligonucleotides may interact with
nucleic acid or nonnucleic
acid receptors; however, rational design of
oligonucleotide drugs to interact with
nucleic acid receptors is significantly simpler because the factors that determine affinity and selectivity are better understood. Recent progress demonstrates that this information can be coupled to rapid advances in the medicinal chemistry of
oligonucleotides to create new generations of
oligonucleotide drugs with dramatically improved properties. The purposes of this review are to place
oligonucleotide therapeutics in the context of modern molecular
drug discovery and to summarize progress in understanding the pharmacodynamic properties of
oligonucleotides designed to bind to
nucleic acid receptors. The pharmacokinetic and toxicologic properties of
oligonucleotides have been reviewed recently (1-4). The activities of
oligonucleotides that bind to nonnucleic
acid receptors will be considered in future reviews.