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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.

Elucidating dynamics in transition-metal distribution and localization under physiological and pathophysiological conditions is central to our understanding of metal-ion regulation. In this Forum A...

International audience; Recent developments in Mn biology have added new physiological and pathophysiological roles of this essential metal ion to the already existing repertoire of indispensable biological roles of Mn ions. Notably, the discovery of Mn2+ specific transporters, maladies related to mutations in these transporters, and evidence of the role of labile Mn2+ species as anti-oxidants have initiated studies targeted at elucidating Mn ion regulation and pathways implicated in pathological conditions. Closely inter-linked with the quest for understanding metal ion homeostasis are basic questions like “How are metal ions installed in their correct biological addresses where they need to function?” and “Are dynamic changes in metal ion distribution functionally relevant?” These questions become more critical in the context of Mn2+ ions, which have inherently low binding affinities toward most ligands and hence would always face competing metal ions in the biological milieu. In the emerging context of functional roles of the labile Mn2+ ion pool, the development of chemical tools and techniques that can provide information on the location, distribution and dynamic changes in these parameters under physiological and pathophysiological conditions becomes imperative. In this frontier article, we discuss the challenges that had left Mn2+ ions lagging behind in the race for the development of chemical tools and recent approaches that addressed these challenges to develop tools and techniques that can illuminate Mn ions in living systems.