Copper ions are essential for
biological function yet are severely detrimental when present in excess. At the molecular level,
copper ions catalyze the production of
hydroxyl radicals that can irreversibly alter essential bio-molecules. Hence, selective
copper chelators that can remove excess
copper ions and alleviate oxidative stress will help assuage
copper-overload diseases. However, most currently available
chelators are non-specific leading to multiple undesirable side-effects. The challenge is to build
chelators that can bind to
copper ions with high affinity but leave the levels of essential
metal ions unaltered. Here we report the design and development of redox-state selective Cu ion
chelators that have 108 times higher conditional stability constants toward Cu2+ compared to both Cu+ and other biologically relevant
metal ions. This unique selectivity allows the specific removal of Cu2+
ions that would be available only under pathophysiological
metal overload and oxidative stress conditions and provides access to effective removal of the aberrant redox-cycling Cu ion pool without affecting the essential non-redox cycling Cu+ labile pool. We have shown that the
chelators provide distinct protection against
copper-induced oxidative stress in vitro and in live cells via selective Cu2+ ion chelation. Notably, the
chelators afford significant reduction in Cu-induced oxidative damage in Atp7a-/-
Menkes disease model cells that have endogenously high levels of Cu
ions. Finally, in vivo testing of our
chelators in a live zebrafish larval model demonstrate their protective properties against
copper-induced oxidative stress.