{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T04:00:31Z","timestamp":1794369631998,"version":"4.9.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T00:00:00Z","timestamp":1516665600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T00:00:00Z","timestamp":1516665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase,\n                    <jats:italic>ATP7B<\/jats:italic>\n                    , 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\u00a0\u2013\u00a0D-penicillamine, trientine, 2,3-dimercapto-1-propanol,\n                    <jats:italic>meso<\/jats:italic>\n                    -2,3-dimercaptosuccinate and tetrathiomolybdate\u00a0\u2013\u00a0by 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, \u03b1-lipoic acid, may be suitable for the treatment of Wilson disease. Our hypothesis is supported by cell culture experiments where \u03b1-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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-19873-2","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T11:42:43Z","timestamp":1516189363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. \u03b1-Lipoic acid as a potential anti-copper agent"],"prefix":"10.1038","volume":"8","author":[{"given":"Julia","family":"Smirnova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Kabin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivar","family":"J\u00e4rving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Bragina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vello","family":"T\u00f5ugu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Plitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peep","family":"Palumaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,1,23]]},"reference":[{"key":"19873_CR1","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/ng1293-327","volume":"5","author":"PC Bull","year":"1993","unstructured":"Bull, P. C., Thomas, G. R., Rommens, J. M., Forbes, J. R. & Cox, D. W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5, 327\u2013337, https:\/\/doi.org\/10.1038\/ng1293-327 (1993).","journal-title":"Nat Genet"},{"key":"19873_CR2","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/ng1293-344","volume":"5","author":"RE Tanzi","year":"1993","unstructured":"Tanzi, R. E. et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5, 344\u2013350, https:\/\/doi.org\/10.1038\/ng1293-344 (1993).","journal-title":"Nat Genet"},{"key":"19873_CR3","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/0925-4439(94)00072-X","volume":"1270","author":"K Terada","year":"1995","unstructured":"Terada, K. et al. Copper incorporation into ceruloplasmin in rat livers. Biochim Biophys Acta 1270, 58\u201362 (1995).","journal-title":"Biochim Biophys Acta"},{"key":"19873_CR4","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1074\/jbc.273.3.1815","volume":"273","author":"K Terada","year":"1998","unstructured":"Terada, K. et al. Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA. J Biol Chem 273, 1815\u20131820 (1998).","journal-title":"J Biol Chem"},{"key":"19873_CR5","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0014-5793(99)00319-1","volume":"448","author":"K Terada","year":"1999","unstructured":"Terada, K. et al. Biliary excretion of copper in LEC rat after introduction of copper transporting P-type ATPase, ATP7B. FEBS Lett 448, 53\u201356 (1999).","journal-title":"FEBS Lett"},{"key":"19873_CR6","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jceh.2013.06.002","volume":"3","author":"M Patil","year":"2013","unstructured":"Patil, M., Sheth, K. A., Krishnamurthy, A. C. & Devarbhavi, H. A review and current perspective on Wilson disease. J Clin Exp Hepatol 3, 321\u2013336, https:\/\/doi.org\/10.1016\/j.jceh.2013.06.002 (2013).","journal-title":"J Clin Exp Hepatol"},{"key":"19873_CR7","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/0002-9343(56)90066-3","volume":"21","author":"JM Walshe","year":"1956","unstructured":"Walshe, J. M. Penicillamine, a new oral therapy for Wilson\u2019s disease. Am J Med 21, 487\u2013495 (1956).","journal-title":"Am J Med"},{"key":"19873_CR8","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1002\/1531-8257(199907)14:4<545::AID-MDS1001>3.0.CO;2-U","volume":"14","author":"JM Walshe","year":"1999","unstructured":"Walshe, J. M. Penicillamine: the treatment of first choice for patients with Wilson\u2019s disease. Mov Disord 14, 545\u2013550 (1999).","journal-title":"Mov Disord"},{"key":"19873_CR9","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1002\/hep.22261","volume":"47","author":"EA Roberts","year":"2008","unstructured":"Roberts, E. A. & Schilsky, M. L. & American Association for Study of Liver Diseases. Diagnosis and treatment of Wilson disease: an update. Hepatology 47, 2089\u20132111, https:\/\/doi.org\/10.1002\/hep.22261 (2008).","journal-title":"Hepatology"},{"key":"19873_CR10","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/S0140-6736(82)92201-2","volume":"1","author":"JM Walshe","year":"1982","unstructured":"Walshe, J. M. Treatment of Wilson\u2019s disease with trientine (triethylene tetramine) dihydrochloride. Lancet 1, 643\u2013647 (1982).","journal-title":"Lancet"},{"key":"19873_CR11","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1093\/brain\/74.1.10","volume":"74","author":"JN Cumings","year":"1951","unstructured":"Cumings, J. N. The effects of B.A.L. in hepatolenticular degeneration. Brain 74, 10\u201322 (1951).","journal-title":"Brain"},{"key":"19873_CR12","doi-asserted-by":"publisher","first-page":"322","DOI":"10.2174\/1570159X14666151130222427","volume":"14","author":"WJ Li","year":"2016","unstructured":"Li, W. J., Chen, C., You, Z. F., Yang, R. M. & Wang, X. P. Current Drug Managements of Wilson\u2019s Disease: From West to East. Curr Neuropharmacol 14, 322\u2013325 (2016).","journal-title":"Curr Neuropharmacol"},{"key":"19873_CR13","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.3390\/ijerph7072745","volume":"7","author":"SJ Flora","year":"2010","unstructured":"Flora, S. J. & Pachauri, V. Chelation in metal intoxication. Int J Environ Res Public Health 7, 2745\u20132788, https:\/\/doi.org\/10.3390\/ijerph7072745 (2010).","journal-title":"Int J Environ Res Public Health"},{"key":"19873_CR14","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.tox.2007.02.016","volume":"234","author":"JP Rooney","year":"2007","unstructured":"Rooney, J. P. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology 234, 145\u2013156, https:\/\/doi.org\/10.1016\/j.tox.2007.02.016 (2007).","journal-title":"Toxicology"},{"key":"19873_CR15","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1001\/archneur.60.3.379","volume":"60","author":"GJ Brewer","year":"2003","unstructured":"Brewer, G. J. et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 60, 379\u2013385 (2003).","journal-title":"Arch Neurol"},{"key":"19873_CR16","doi-asserted-by":"publisher","first-page":"S88","DOI":"10.1016\/S0168-8278(17)30440-3","volume":"66","author":"KH Weiss","year":"2017","unstructured":"Weiss, K. H. et al. WTX101 in patients newly diagnosed with Wilson disease: final results of a global, prospective phase 2 trial. J Hepatol 66, S88 (2017).","journal-title":"J Hepatol"},{"key":"19873_CR17","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.4254\/wjh.v7.i29.2859","volume":"7","author":"KI Rodriguez-Castro","year":"2015","unstructured":"Rodriguez-Castro, K. I., Hevia-Urrutia, F. J. & Sturniolo, G. C. Wilson\u2019s disease: A review of what we have learned. World J Hepatol 7, 2859\u20132870, https:\/\/doi.org\/10.4254\/wjh.v7.i29.2859 (2015).","journal-title":"World J Hepatol"},{"key":"19873_CR18","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nature09018","volume":"465","author":"L Banci","year":"2010","unstructured":"Banci, L. et al. Affinity gradients drive copper to cellular destinations. Nature 465, 645\u2013648, https:\/\/doi.org\/10.1038\/nature09018 (2010).","journal-title":"Nature"},{"key":"19873_CR19","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.pep.2006.11.014","volume":"53","author":"A Voronova","year":"2007","unstructured":"Voronova, A. et al. Cox17, a copper chaperone for cytochrome c oxidase: expression, purification, and formation of mixed disulphide adducts with thiol reagents. 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Res Commun Mol Pathol Pharmacol 88, 187\u2013195 (1995).","journal-title":"Res Commun Mol Pathol Pharmacol"},{"key":"19873_CR22","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S0162-0134(00)00212-9","volume":"84","author":"A Krezel","year":"2001","unstructured":"Krezel, A. et al. Coordination of heavy metals by dithiothreitol, a commonly used thiol group protectant. Journal of Inorganic Biochemistry 84, 77\u201388, https:\/\/doi.org\/10.1016\/S0162-0134(00)00212-9 (2001).","journal-title":"Journal of Inorganic Biochemistry"},{"key":"19873_CR23","doi-asserted-by":"publisher","first-page":"7526","DOI":"10.1158\/1078-0432.CCR-08-0315","volume":"14","author":"SA Lowndes","year":"2008","unstructured":"Lowndes, S. A. et al. Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors. Clin Cancer Res 14, 7526\u20137534, https:\/\/doi.org\/10.1158\/1078-0432.CCR-08-0315 (2008).","journal-title":"Clin Cancer Res"},{"key":"19873_CR24","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1158\/1078-0432.CCR-06-0171","volume":"12","author":"JC Juarez","year":"2006","unstructured":"Juarez, J. C. et al. Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin Cancer Res 12, 4974\u20134982, https:\/\/doi.org\/10.1158\/1078-0432.CCR-06-0171 (2006).","journal-title":"Clin Cancer Res"},{"key":"19873_CR25","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/S0891-5849(96)00269-9","volume":"22","author":"L Packer","year":"1997","unstructured":"Packer, L., Tritschler, H. J. & Wessel, K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 22, 359\u2013378 (1997).","journal-title":"Free Radic Biol Med"},{"key":"19873_CR26","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/j.bbagen.2009.07.026","volume":"1790","author":"KP Shay","year":"2009","unstructured":"Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R. & Hagen, T. M. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 1790, 1149\u20131160, https:\/\/doi.org\/10.1016\/j.bbagen.2009.07.026 (2009).","journal-title":"Biochim Biophys Acta"},{"key":"19873_CR27","first-page":"438","volume":"11","author":"SF da Costa","year":"1961","unstructured":"da Costa, S. F., Rodrigues, E. M., da Silva, J. A., Relvas, M. E. & Halpern, M. J. Zur biochemischen Pathologie der Wilsonscher Krankheit. 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Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines. World J Gastroenterol 22, 4109\u20134119, https:\/\/doi.org\/10.3748\/wjg.v22.i16.4109 (2016).","journal-title":"World J Gastroenterol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-19873-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-19873-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-19873-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T20:25:00Z","timestamp":1671567900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-19873-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,23]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["19873"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-19873-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,23]]},"assertion":[{"value":"27 October 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1463"}}