Aquaporin Inhibition by Gold(III) Compounds: New Insights

Authors

  • Ana Paula Martins,

    1. Research Institute for Medicines & Pharmaceutical Sciences (iMed.UL), Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
    2. Dept. of Biochemistry & Human Biology, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1649-019 (Portugal)
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  • Dr. Antonella Ciancetta,

    1. Molecular Modeling Section (MMS), Department of Pharmaceutical & Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova (Italy)
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  • Andreia de Almeida,

    1. Dept. of Pharmacokinetics, Toxicology & Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen (The Netherlands)
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  • Dr. Alessandro Marrone,

    1. Department of Pharmaceutical Sciences, G. d'Annunzio University of Chieti-Pescara, Via dei Vestini, 66013 Chieti (Italy)
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  • Prof. Nazzareno Re,

    1. Department of Pharmaceutical Sciences, G. d'Annunzio University of Chieti-Pescara, Via dei Vestini, 66013 Chieti (Italy)
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  • Prof. Graça Soveral,

    Corresponding author
    1. Research Institute for Medicines & Pharmaceutical Sciences (iMed.UL), Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
    2. Dept. of Biochemistry & Human Biology, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1649-019 (Portugal)
    • Research Institute for Medicines & Pharmaceutical Sciences (iMed.UL), Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
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  • Dr. Angela Casini

    Corresponding author
    1. Dept. of Pharmacokinetics, Toxicology & Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen (The Netherlands)
    • Dept. of Pharmacokinetics, Toxicology & Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen (The Netherlands)
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Abstract

Aquaporins (AQPs) are membrane water/glycerol channels with essential roles in biological systems, as well as being promising targets for therapy and imaging. Using a stopped-flow method, a series of gold(III), platinum(II) and copper(II) complexes bearing nitrogen donor ligands, such as 1,10-phenatroline, 2,2′-bipyridine, 4,4′-dimethyl-2,2′-bipyridine, 4,4′-diamino-2,2′-bipyridine and 2,2′;6′,2“-terpyridine, were evaluated in human red blood cells expressing AQP1 and AQP3, responsible for water and glycerol movement, respectively. The results showed that the gold(III) complexes selectively modulate AQP3 over AQP1. Molecular modeling and density functional theory (DFT) calculations were subsequently performed to rationalize the observations and to investigate the possible molecular mechanism through which these gold compounds act on their putative target (AQP3). In the absence of any crystallographic data, a previously reported homology model was used for this purpose. Combined, the findings of this study show that potent and selective modulation of these solute channels is possible, however further investigation is required into the selectivity of this class of agents against all AQP isoforms and their potential therapeutic uses.

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