Oligonucleotide analogues as potential chemotherapeutic agents

Oligonucleotides specifically bind to complementary sequences of either genomic DNA or genomic RNA through hydrogen bonding of base pairs. In principle, relatively short oligomers (less than 20 bases) can specifically hybridize with DNA or RNA and thus be used for novel drug design strategies involving targeted interference of genetic expression at the level of transcription or translation. Conceivable chemotherapeutic applications predicated on sequence-specific hybridization ("antisense" inhibition) require oligonucleotide analogues that are resistant to in vivo degradation by enzymes such as nucleases. Nuclease-resistant analogues having modified internucleoside linkages (e.g., methylphosphonates or phosphorothioates) or modified nucleosides (e.g., 2'-0-methylribose or alpha-anomers) are now readily available by means of automated synthesis, and there are various classes of pendant groups (e.g., alkylating or intercalating agents) that can be attached to increase the efficacy of these analogues. The present account reviews this area of research by classifying structures and mechanisms of action, with comments on stereochemistry. Biological studies are briefly summarized, and pharmaceutically related topics of interest are noted.