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Issue 41, 2018
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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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Supplementary files

Article information


Submitted
11 Sep 2018
Accepted
29 Sep 2018
First published
02 Oct 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2018,9, 7916-7930
Article type
Edge Article

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

A. Rakshit, K. Khatua, V. Shanbhag, P. Comba and A. Datta, Chem. Sci., 2018, 9, 7916
DOI: 10.1039/C8SC04041A

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    [Original citation] - Published by The Royal Society of Chemistry.

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