Martins, Ana PaulaMarrone, AlessandroCiancetta, AntonellaGalán Cobo, AnaEchevarría, MiriamMoura, Teresa FRe, NazzarenoCasini, AngelaSoveral, Graça2013-03-132013-03-132012-05-05Martins AP, Marrone A, Ciancetta A, Galán Cobo A, Echevarría M, Moura TF, et al. Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound. PLoS ONE; 7(5):e37435http://hdl.handle.net/10668/829Journal Article; Research Support, Non-U.S. Gov't;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.enAcuaporina 3GlicerolAgua CorporalCompuestos de OroMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Porins::Aquaporins::Aquaglyceroporins::Aquaporin 3Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Biological Transport::Cell Membrane PermeabilityMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug DiscoveryMedical Subject Headings::Anatomy::Cells::Blood Cells::ErythrocytesMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Alcohols::Sugar Alcohols::GlycerolMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Gold CompoundsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, MolecularMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Molecular StructureMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::PC12 CellsMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein BindingMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular ConformationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::RatsMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Hydroxides::WaterMedical Subject Headings::Organisms::Eukaryota::Animalsresearch article22624030open access10.1371/journal.pone.00374351932-6203PMC3356263