1. Targeting Aquaporin Function: Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound
- Author
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Teresa F. Moura, Alessandro Marrone, Graça Soveral, Angela Casini, Ana Galán Cobo, Miriam Echevarría, Nazzareno Re, Antonella Ciancetta, Ana Paula Martins, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medicinal Chemistry and Bioanalysis (MCB), Nanomedicine & Drug Targeting, [Martins,AP, Moura,TF, Soveral,G] REQUIMTE, Departamento de Química, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal. [Marrone,A, Ciancetta,A, Re,N] Dipartimento di Scienze del Farmaco Università G. d’Annunzio, Chieti, Italy. [Galán Cobo,A, Echevarría,M] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville. Spain. [Casini,A] Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands. [Soveral,G] Departamento de Bioquímica e Biologia Humana, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal., and Fundaçao para a Ciência e a Tecnologia, Portugal, through a Ph.D. fellowship to APM (SFRH/BD/65046/2009). A. Casini thanks the University of Groningen (Rosalind Franklin fellowship). The authors thank COST CM0902 for financial support.
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Glycerol ,Models, Molecular ,Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::PC12 Cells [Medical Subject Headings] ,Cell Membrane Permeability ,Erythrocytes ,Protein Conformation ,lcsh:Medicine ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Porins::Aquaporins::Aquaglyceroporins::Aquaporin 3 [Medical Subject Headings] ,Plasma protein binding ,01 natural sciences ,Biochemistry ,PC12 Cells ,Ion Channels ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Transmembrane Transport Proteins ,Anatomy::Cells::Blood Cells::Erythrocytes [Medical Subject Headings] ,Compuestos de Oro ,Protein structure ,Computational Chemistry ,BASOLATERAL MEMBRANE ,Drug Discovery ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular [Medical Subject Headings] ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,lcsh:Science ,Chemicals and Drugs::Organic Chemicals::Alcohols::Sugar Alcohols::Glycerol [Medical Subject Headings] ,0303 health sciences ,Multidisciplinary ,Molecular Structure ,Chemistry ,Glicerol ,Applied Chemistry ,SOLUTION CHEMISTRY ,3. Good health ,GOLD(III) COMPOUNDS ,SELECTIVITY ,Blood Chemistry ,Phenomena and Processes::Metabolic Phenomena::Metabolism::Biological Transport::Cell Membrane Permeability [Medical Subject Headings] ,Medicine ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation [Medical Subject Headings] ,Research Article ,Biotechnology ,Protein Binding ,Drugs and Devices ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery [Medical Subject Headings] ,Drug Research and Development ,Biophysics ,Aquaporin ,010402 general chemistry ,Aquaporins ,NO ,03 medical and health sciences ,Phenomena and Processes::Chemical Phenomena::Molecular Structure [Medical Subject Headings] ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding [Medical Subject Headings] ,In vivo ,Chemical Biology ,Animals ,Humans ,Chemicals and Drugs::Inorganic Chemicals::Hydroxides::Water [Medical Subject Headings] ,Homology modeling ,Biology ,030304 developmental biology ,Aquaporin 3 ,lcsh:R ,COLLECTING DUCT ,Proteins ,Water ,Periplasmic space ,WATER PERMEABILITY ,Acuaporina 3 ,AQP3 ,0104 chemical sciences ,Rats ,Agua Corporal ,Transmembrane Proteins ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats [Medical Subject Headings] ,Docking (molecular) ,CHANNEL PROTEINS ,FORCE-FIELD ,lcsh:Q ,PROTEIN HOMOLOGY DETECTION ,Aquaglyceroporin-3 ,Chemicals and Drugs::Inorganic Chemicals::Gold Compounds [Medical Subject Headings] ,Medicinal Chemistry ,Organogold Compounds ,Cysteine - Abstract
Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC 50 = 0.8±0.08 μM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development. © 2012 Martins et al., This work was supported from Fundação para a Ciência e a Tecnologia, Portugal, through a Ph.D. fellowship to APM (SFRH/BD/65046/2009). A. Casini thanks the University of Groningen (Rosalind Franklin fellowship). The authors thank COST CM0902 for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Published
- 2012