DNA hybridization reactions, discovered and explored in the early 1960s and 70's, exhibit nearly absolute specificity. Researchers recognized that this specificity might make it possible to develop DNA based diagnostic and therapeutic agents. In 1977 Paterson and coworkers discovered hybrid-arrest of translation. Anti-sense oligonucleotides, RNAs and cDNAs have now been shown to hybridize to and inhibit the translation of specific mRNAs both in vitro and in vivo. Such specific translation inhibiting compounds are useful in studying the function of particular mRNAs in the living cell and could potentially be used to selectively block the growth of viruses and bacteria. The major difficulty is that they are large polyanions which are poorly taken up by cells and are subject to rapid degradation by nucleases. Synthetic oligonucleotide phosphotriesters (PTEs) and methylphosphonates are non-ionic, lipophilic molecules which are stable to nucleases and well taken up by living cells. DNA phosphotriesters hybridize to both RNA and DNA in vitro and can selectively inhibit in vitro translation. Thus defined sequence PTE's would be useful in the study of mRNA function and processing in vivo. In addition, these agents could, if proven safe and effective, be used as specific and designable antiviral and antibiotic agents.
