Prodrug approaches of nucleotides and oligonucleotides.

The main threshold for the therapeutic applications of nucleotides and oligonucleotides is their ionic structure which implies poor cellular uptake and unfavorable pharmacokinetic parameters. To circumvent these problems, the anionic phosphate moieties may be temporarily masked with enzymolabile protecting groups to form neutral pronucleotides or pro-oligonucleotides. In cells, enzymes cleave the protecting groups and release the parent drug. Several prodrug strategies have been developed, but the kinetics and mechanisms of the deprotection of potential prodrug candidates are still often poorly known. The purpose of the present review is to summarize the current knowledge on the chemical aspects of alternative prodrug strategies at nucleotide and oligonucleotide level.