Prodrug Approaches of Nucleotides and Oligonucleotides

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