Objective: The review covers basic principles of the prodrug strategy applied to antiviral nucleoside
drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to
transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the
most important representatives (compounds under clinical investigations or available on the market) are
described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine,
valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides.
Method: A special attention is paid to acyclic nucleoside phosphonates, where the phosphonic acid residue
is esterified with a side-chain hydroxyl group of appropriate amino acid (serine, tyrosine) which can
be used as single amino acid or as a part of dipeptides further modified on the terminal carboxyl function.
The most advantageous pharmacokinetic profile and the best oral bioavailability were found in tyrosinebased
Results & Conclusion: Studies were performed successfully on 1-(S)-[3-hydroxy-2-(phosphonomethoxy)
propyl]cytosine (cidofovir), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine and some (R)-2-
(phosphonomethoxy)propyl and 2-(phosphonomethoxy)ethyl derivatives including adefovir.