title: Reactivity of Cys4 zinc finger domains with gold(III) complexes: insights into the formation of "gold fingers".
abstract: Gold(I) complexes such as auranofin or aurothiomalate have been used as therapeutic agents for the treatment of rheumatoid arthritis for several decades. Several gold(I) and gold(III) complexes have also shown in vitro anticancer properties against human cancer cell lines, including cell lines resistant to cisplatin. Because of the thiophilicity of gold, cysteine-containing proteins appear as likely targets for gold complexes. Among them, zinc finger proteins have attracted attention and, recently, gold(I) and gold(III) complexes have been shown to inhibit poly(adenosine diphosphate ribose)polymerase-1 (PARP-1), which is an essential protein involved in DNA repair and in cancer resistance to chemotherapies. In this Article, we characterize the reactivity of the gold(III) complex [Au(III)(terpy)Cl]Cl2 (Auterpy) with a model of Zn(Cys)4 "zinc ribbon" zinc finger by a combination of absorption spectroscopy, circular dichroism, mass spectrometry, high-performance liquid chromatography analysis, and X-ray absorption spectroscopy. We show that the Zn(Cys)4 site of Zn·LZR is rapidly oxidized by Auterpy to form a disulfide bond. The Zn(2+) ion is released, and the two remaining cysteines coordinate the Au(+) ion that is produced during the redox reaction. Subsequent oxidation of these cysteines can take place in conditions of excess gold(III) complex. In the presence of excess free thiols mimicking the presence of glutathione in cells, mixing of the zinc finger model and gold(III) complex yields a different product: complex (Au(I))2·LZR with two Au(+) ions bound to cysteines is formed. Thus, on the basis of detailed speciation and kinetic measurements, we demonstrate herein that the destruction of Zn(Cys)4 zinc fingers by gold(III) complexes to achieve the formation of "gold fingers" is worth consideration, either directly or mediated by reducing agents.
authors.affiliation: †Université Grenoble Alpes, LCBM/PMB, F-38000 Grenoble, France.|‡CNRS, LCBM/PMB, UMR 5249, F-38000 Grenoble, France.|§CEA, IRTSV-LCBM, PMB, F-38000 Grenoble, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jacques
authors.affiliation: ⊥Université Grenoble Alpes, INAC-SCIB, F-38000 Grenoble, France.|∥CEA, INAC-SCIB, F-38000 Grenoble, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Lebrun
authors.affiliation: ¶Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.affiliation: ≠BM30B/FAME beamline, European Synchrotron Radiation Facility (ESRF), F-38000 Grenoble, France.|#Observatoire des Sciences de l'Univers de Grenoble, UMS 832, CNRS, Université Joseph Fourier, F-38000 Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Kieffer
authors.affiliation: ≠BM30B/FAME beamline, European Synchrotron Radiation Facility (ESRF), F-38000 Grenoble, France.|#Observatoire des Sciences de l'Univers de Grenoble, UMS 832, CNRS, Université Joseph Fourier, F-38000 Grenoble, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Proux
authors.affiliation: †Université Grenoble Alpes, LCBM/PMB, F-38000 Grenoble, France.|‡CNRS, LCBM/PMB, UMR 5249, F-38000 Grenoble, France.|§CEA, IRTSV-LCBM, PMB, F-38000 Grenoble, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Latour
authors.affiliation: †Université Grenoble Alpes, LCBM/PMB, F-38000 Grenoble, France.|‡CNRS, LCBM/PMB, UMR 5249, F-38000 Grenoble, France.|§CEA, IRTSV-LCBM, PMB, F-38000 Grenoble, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sénèque
mesh_terms: D006801:Humans; D015394:Molecular Structure; D050607:Organogold Compounds / Q000737:chemistry*; D016335:Zinc Fingers
chemical_list: D050607:Organogold Compounds