Page - (000220) - in Biomedical Chemistry: Current Trends and Developments

Prodrug strategies have arguably been successful for a number of clinically-used therapeutic agents. However, prodrug research encounters various challenges and requires additional work in preclinical and clinical settings, much of which can be attributed to understanding the bioconversion mechanisms of prodrugs. Many enzymes involved in prodrug activation are subject to interindividual variabilities in their activities. The main factors contributing to this variability are intrinsic, especially polymorphisms in the genes encoding the enzymes, but can also be extrinsic (i.e. interactions caused by other drugs and xenobiotics). Both intrinsic and extrinsic factors may cause insufficient or excessive conversion of the prodrugs into their active forms. Moreover, interspecies differences in enzyme activation represent another hurdle to the prediction of human disposition of certain prodrugs (Hutunen, 2011). The enzymatic hydrolysis of amino acid esters and amides by various hydrolases (e.g. esterases and/or peptidases) is far more effective than chemical hydrolysis. The half-lives of prodrugs are usually several orders of magnitude shorter in blood or tissue homogenates than in aqueous solutions. Often the activating enzymes are unidentified. However, it has been suggested that the biphenyl hydrolase-like protein human valacyclovirase (VACVase) is at least partly responsible for hydrolysis of the prodrugs valacyclovir and valganciclovir (Fig. 3.1.6) and might be involved in the activation of other amino acid prodrugs as well (Kim, 2003; 2004; Lai, 2004). As the specificity of this enzyme resides mainly in the amino acid acyl promoiety (and to a lesser extent in the alcohol moiety of a parent drug) and that the α-amino group in the substrate is important for activity, the enzyme can be better defined as an α-amino acid ester prodrug-activating enzyme (Burnette, 1995; Lai, 2004). VACVase prefers small, hydrophobic (valine, proline) or aromatic side chains (phenylalanine) over the charged amino acids (lysine, aspartic acid). It has shown clear stereoselectivity for L-valine over D- valine prodrugs irrespective of the parent drug while exhibiting comparable hydrolytic activity toward D-phenylalanine and L- phenylalanine esters, as indicated in a study of various nucleoside analogue prodrugs (Kim, 2004). The success of valacyclovir and valganciclovir has proved that an L-valine prodrug approach is a very