Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent

Abstract Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes co...

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Autores principales:	Julia Smirnova, Ekaterina Kabin, Ivar Järving, Olga Bragina, Vello Tõugu, Thomas Plitz, Peep Palumaa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5d926ca94e3f422baf2d72ab51c8f33f
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spelling	oai:doaj.org-article:5d926ca94e3f422baf2d72ab51c8f33f2021-12-02T15:08:23ZCopper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent10.1038/s41598-018-19873-22045-2322https://doaj.org/article/5d926ca94e3f422baf2d72ab51c8f33f2018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19873-2https://doaj.org/toc/2045-2322Abstract Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized. Here we determined the Cu(I)-binding affinities of five major de-coppering drugs – D-penicillamine, trientine, 2,3-dimercapto-1-propanol, meso-2,3-dimercaptosuccinate and tetrathiomolybdate – by exploring their ability to extract Cu(I) ions from two Cu(I)-binding proteins, the copper chaperone for cytochrome c oxidase, Cox17, and metallothionein. We report that the Cu(I)-binding affinity of these drugs varies by four orders of magnitude and correlates positively with the number of sulfur atoms in the drug molecule and negatively with the number of atoms separating two SH groups. Based on the analysis of structure-activity relationship and determined Cu(I)-binding affinity, we hypothesize that the endogenous biologically active substance, α-lipoic acid, may be suitable for the treatment of Wilson disease. Our hypothesis is supported by cell culture experiments where α-lipoic acid protected hepatic cells from copper toxicity. These results provide a basis for elaboration of new generation drugs that may provide better therapeutic outcomes.Julia SmirnovaEkaterina KabinIvar JärvingOlga BraginaVello TõuguThomas PlitzPeep PalumaaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julia Smirnova Ekaterina Kabin Ivar Järving Olga Bragina Vello Tõugu Thomas Plitz Peep Palumaa Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
description	Abstract Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized. Here we determined the Cu(I)-binding affinities of five major de-coppering drugs – D-penicillamine, trientine, 2,3-dimercapto-1-propanol, meso-2,3-dimercaptosuccinate and tetrathiomolybdate – by exploring their ability to extract Cu(I) ions from two Cu(I)-binding proteins, the copper chaperone for cytochrome c oxidase, Cox17, and metallothionein. We report that the Cu(I)-binding affinity of these drugs varies by four orders of magnitude and correlates positively with the number of sulfur atoms in the drug molecule and negatively with the number of atoms separating two SH groups. Based on the analysis of structure-activity relationship and determined Cu(I)-binding affinity, we hypothesize that the endogenous biologically active substance, α-lipoic acid, may be suitable for the treatment of Wilson disease. Our hypothesis is supported by cell culture experiments where α-lipoic acid protected hepatic cells from copper toxicity. These results provide a basis for elaboration of new generation drugs that may provide better therapeutic outcomes.
format	article
author	Julia Smirnova Ekaterina Kabin Ivar Järving Olga Bragina Vello Tõugu Thomas Plitz Peep Palumaa
author_facet	Julia Smirnova Ekaterina Kabin Ivar Järving Olga Bragina Vello Tõugu Thomas Plitz Peep Palumaa
author_sort	Julia Smirnova
title	Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
title_short	Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
title_full	Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
title_fullStr	Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
title_full_unstemmed	Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent
title_sort	copper(i)-binding properties of de-coppering drugs for the treatment of wilson disease. α-lipoic acid as a potential anti-copper agent
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/5d926ca94e3f422baf2d72ab51c8f33f
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Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent

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