Abstract

Catalytic metallodrugs combine a reactive metal center with a recognition motif for a structured nucleic acid or protein therapeutic target, and demonstrate effective and selective cleavage or modification chemistry. Reactivity is highly dependent on factors that include metal reduction potential, coordination unsaturation, overall charge, the ability of the metal complexes to facilitate generation of ROS , and the degree to which these ROS are either metal-coordinated or diffusible. In contrast to nucleic acid targets that undergo backbone scission, enzyme inactivation appears to arise through oxidative damage to amino acid sidechains in the active site. Reactivity stems primarily from metal associated reactive oxygen species. Catalytic metallodrugs embody several unique advantages over traditional drug “inhibitors” – namely, the target is eliminated, multiturnover activity allows a sub-stoichiometric concentration of catalyst relative to target, improved selectivity, and reduced potential for resistance. Application of this strategy to HCV , HIV, bacterial and cardiovascular protein and RNA targets will be discussed, including solution and cellular assays, and studies of animal models.