Antiviral nucleotide drug delivery via amino acid phosphoramidates

Our laboratory has developed a strategy for the delivery of antiviral nu cleosides via hydrophobic amino acid phorphoramidate prodrugs. Synthetic methodologies have been developed for the construction of phosphoramidate amino acid nucleosides and biological and biochemical experiments have been conducted. The phosphomonoester amidates were shown to be water soluble and indefinitely stable in human blood. Several of the antiviral phosphoramidates have demonstrated greater potency than the parent nucleosides, but with little or no associated cytotoxicity toward human cell cultures or a.nimals. Mechanistic studies attempting to characterize the activity of these unique compounds have provided supporting evidence for direct intracellular P-N bond cleavage by T lymphocytes. In addition, using the rat as a model system, we have observed that amino acid phosphomonoester amidates of AZT have a significantly longer in vivo half life than the parent nucleoside, suggesting that phosphoramidates maybe able to significantly enhance the pharamcokinetic parameters for nucleoside based drugs from minutes to days.