Target-directed catalytic metallodrugs

Abstract

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements.

Diisopropyl fluorophosphate (DFP) degradation activity using transition metal–dipicolylamine complexes

“…The ability of metal ions incorporated in natural enzymes catalytically hydrolyzing phosphate esters such as RNA and DNA shed a light to studies to develop synthetic metal–organic ligand complexes for decades Mechanistic insights from artificial enzymes studies have provided substantial information on natural. Enzyme systems, allowing us to design better artificial enzymes (e.g., restriction enzymes) . More importantly, some group of artificial enzymes can be used for the decomposition of pesticides and chemical agents, which is of high significance in military and environmental sections.…”

“…Enzyme systems, allowing us to design better artificial enzymes (e.g., restriction enzymes). [5][6][7][8][9][10][11] More importantly, some group of artificial enzymes can be used for the decomposition of pesticides and chemical agents, which is of high significance in military and environmental sections. In particular, the decontamination reactivity of complexes between various metal ions and organic ligands have been widely investigated for catalytic hydrolysis of organophosphorus compounds (e.g., nerve agents).…”

Metal-binding and redox properties of substituted linear and cyclic ATCUN motifs

“…ATCUN motifs are tripeptides with a free N-terminus and histidine in the third position, and these motifs bind several divalent transition metal ions with high affinity [1]. Cu(II) and Ni(II) complexes of ATCUN peptides have been used as oxidation catalysts for site-specific DNA cleavage and protein cleavage [1-13], protein-protein cross linking [14-16], enzyme inhibitors [17, 18], and metallodrugs [19-21]. ATCUN motifs bind Cu(II) or Ni(II) in a square planar geometry using nitrogens from the N-terminal amine, imidazole, and two backbone amides.…”

Improved Bioactivity of Antimicrobial Peptides by Addition of Amino‐Terminal Copper and Nickel (ATCUN) Binding Motifs

“…[26,27] The ROS-forming ability of the ATCUN motif has been exploited to design catalytic metallodrugs. [24, 25, 28] …”