Issue 15, 2022

A caged imidazopyrazinone for selective bioluminescence detection of labile extracellular copper(ii)

Abstract

Copper is an essential redox-active metal that plays integral roles in biology ranging from enzymatic catalysis to mitochondrial respiration. However, if not adequately regulated, this redox activity has the potential to cause oxidative stress through the production of reactive oxygen species. Indeed, the dysregulation of copper has been associated with a variety of disease states including diabetes, neurodegenerative disorders, and multiple cancers. While increasing tools are being developed for illuminating labile intracellular copper pools and the trafficking pathways in which they are involved, significantly less attention has been given to the analogous extracellular labile pool. To address this gap, we have developed a bioluminescence-based imaging probe, picolinic ester caged-diphenylterazine (pic-DTZ) for monitoring labile, extracellular copper using a coelenterazine-like imidazopyrazinone and the genetically-engineered, marine-based luciferase, nanoluciferase. Unlike the more commonly-used firefly luciferase, nanoluciferase does not require ATP, allowing its application to the extracellular milieu. pic-DTZ demonstrates high metal and oxidation state selectivity for Cu(II) in aqueous buffer as well as selectivity for labile pools over coordinatively inaccessible protein-bound Cu(II). We demonstrate the potential of pic-DTZ as a diagnostic tool in human serum and plasma for copper-associated diseases. Additionally, we apply pic-DTZ to lend insight into the extracellular copper dynamic in anticancer treatments.

Graphical abstract: A caged imidazopyrazinone for selective bioluminescence detection of labile extracellular copper(ii)

Associated articles

Supplementary files

Article information

Article type
Edge Article
Submitted
23 dek 2021
Accepted
21 mar 2022
First published
23 mar 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2022,13, 4352-4363

A caged imidazopyrazinone for selective bioluminescence detection of labile extracellular copper(II)

J. J. O'Sullivan, V. Medici and M. C. Heffern, Chem. Sci., 2022, 13, 4352 DOI: 10.1039/D1SC07177G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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