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Cu2+ selective chelators relieve copper-induced oxidative stress in vivo

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Abstract

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.

Graphical abstract: Cu2+ selective chelators relieve copper-induced oxidative stress in vivo

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Publication details

The article was received on 11 Sep 2018, accepted on 29 Sep 2018 and first published on 02 Oct 2018


Article type: Edge Article
DOI: 10.1039/C8SC04041A
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY-NC license
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    Cu2+ selective chelators relieve copper-induced oxidative stress in vivo

    A. Rakshit, K. Khatua, V. Shanbhag, P. Comba and A. Datta, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C8SC04041A

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