While absolutely essential for biological activity, excess redox-active metal ions have been associated with severe neuro-degenerative disorders. A significant route by which excess redox-active metal ions affect cellular function is via the Fenton reaction. Catalytic production of reactive hydroxyl radical from hydrogen peroxide in the presence of Cu+/Cu2+ and Fe2+/Fe3+ leads to permanent modification of cellular lipids, nucleic acids, and proteins. Metal ion chelators can alleviate oxidative stress associated symptoms of metal-induced disorders. However, a major shortcoming of chelation therapy is the non-specific removal of other biologically essential metal ions leading to multiple side-effects. Therefore, cell-permeable metal selective chelators that can specifically remove excess metal ions responsible for oxidative stress will be extremely valuable motifs for chelation therapy.
We have worked on the development of selective cell-permeable chelators for redox-active metal ions with focus on Cu ion chelation. The motivation for our work derives from the fact that while Cu+/Cu2+ ions are absolutely essential for biological activity, excess Cu is implicated in severe neurological and metabolic disorders like Alzheimer’s disease, amyotrophic lateral sclerosis, cancer and Wilson’s disease. We have designed and developed novel Cu2+ selective chelators that have at least 108 times higher cumulative stability constants toward Cu2+ compared to other biologically relevant metal ions and do not remove Cu2+ from metallo-proteins. We have demonstrated that the chelators provide protection against copper-induced oxidative stress in vitro and in live cells. Importantly, the chelators reduce Cu2+ induced oxidative damage in Atp7a−/− cells (generously shared by Prof. Michael J. Petris, University of Missouri) which model genetic copper mis-regulation in Menkes disease. Encouraged by these results, we took the chelators a step forward and tested them in live zebrafish larvae which are established vertebrate models for studying oxidative stress. Our results showed that the chelators could provide efficient protection against copper-induced oxidative stress in vivo in the zebrafish larval model. The results indicate the potential of the selective Cu2+ chelators as scaffolds for development of therapeutics for Cu-overload induced diseases and we are currently working on the development of pro-chelators that can target specific disease conditions and are also developing chelators for other transition metal ion induced disorders.