Please use this identifier to cite or link to this item:
Title: Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.
Authors: Martins, Ana Paula
Marrone, Alessandro
Ciancetta, Antonella
Galán Cobo, Ana
Echevarría, Miriam
Moura, Teresa F
Re, Nazzareno
Casini, Angela
Soveral, Graça
metadata.dc.contributor.authoraffiliation: [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.
Keywords: Acuaporina 3;Glicerol;Agua Corporal;Compuestos de Oro
metadata.dc.subject.mesh: 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::Phenomena and Processes::Metabolic Phenomena::Metabolism::Biological Transport::Cell Membrane Permeability
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery
Medical Subject Headings::Anatomy::Cells::Blood Cells::Erythrocytes
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Alcohols::Sugar Alcohols::Glycerol
Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Gold Compounds
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Molecular Structure
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::PC12 Cells
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats
Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Hydroxides::Water
Medical Subject Headings::Organisms::Eukaryota::Animals
Issue Date: 5-May-2012
Publisher: Public Library of Science
Citation: Martins 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):e37435
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.
Description: Journal Article; Research Support, Non-U.S. Gov't;
metadata.dc.identifier.doi: 10.1371/journal.pone.0037435
ISSN: 1932-6203 (Online)
1932-6203 (Print)
Appears in Collections:01- Artículos - Hospital Virgen del Rocío

Files in This Item:
File Description SizeFormat 
Martins_TargetingAquaporin.pdf821,87 kBAdobe PDFView/Open

This item is protected by original copyright

This item is licensed under a Creative Commons License Creative Commons