Targeting Aquaporin Function: Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound

descriptionPublicationkeyboard_double_arrow_right Article 18 May 2012 Spain, Netherlands, Italy, Spain, Italy English Publisher:Public Library of Science (PLoS)Journal:PLoS ONE, volume 7, page e37435 (eissn: 1932-6203,

Copyright policy )Funded by:FCT | Biological membranes - bi...

Authors: Martins AP; Marrone; A; Ciancetta A; Cobo AG; Echevarria M; Moura TF; +3 Authors

doi: 10.1371/journal.pone.0037435

pmid: 22624030

pmc: PMC3356263

handle: 10261/63080 , 10668/829 , 11441/114921 , 11370/941d0dc8-2f55-4b90-ae5a-bfcda03a293b , 11564/268489 , 11392/2466406

Targeting Aquaporin Function: Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound

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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.

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Keywords

Glycerol, Models, Molecular, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular, Cell Membrane Permeability, Erythrocytes, Protein Conformation, PC12 Cells, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans, Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::PC12 Cells, BASOLATERAL MEMBRANE, Drug Discovery, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Porins::Aquaporins::Aquaglyceroporins::Aquaporin 3, Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Gold Compounds, Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Hydroxides::Water, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding, Molecular Structure, Q, R, GLYCEROL, SOLUTION CHEMISTRY, GOLD(III) COMPOUNDS, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Molecular Structure, Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Biological Transport::Cell Membrane Permeability, Medical Subject Headings::Organisms::Eukaryota::Animals, SELECTIVITY, Medicine, Research Article, Protein Binding, Science, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation, Aquaporins, Animals, Humans, Aquaporin 3, COLLECTING DUCT, Water, WATER PERMEABILITY, AQP3, Medical Subject Headings::Anatomy::Cells::Blood Cells::Erythrocytes, Rats, CHANNEL PROTEINS, FORCE-FIELD, PROTEIN HOMOLOGY DETECTION, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats, Aquaglyceroporin-3, Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Alcohols::Sugar Alcohols::Glycerol, Organogold Compounds

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