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oai:riubu.ubu.es:10259/48742021-11-10T09:38:19Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy Cossu, Claudia Fiore, Michele Baroni, Debora Capurro, Valeria Caci, Emanuela García Valverde, María Quesada Pato, Roberto Moran, Óscar cystic fibrosis ionophore ion transport phospholipid vesicles prodigiosin derivatives Química orgánica Chemistry, Organic Cystic fibrosis (CF) is a genetic lethal disease, originated from the defective function of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel. CF mutations affect CFTR protein through a variety of molecular mechanisms which result in different functional defects. Current therapeutic approaches are targeted to specific groups of patients that share a common functional defect. We seek to develop an innovative therapeutic approach for the treatment of CF using anionophores, small molecules that facilitate the transmembrane transport of anions. We have characterized the anion transport mechanism of a synthetic molecule based on the structure of prodigiosine, a red pigment produced by bacteria. Anionophore-driven chloride efflux from large unilamellar vesicles is consistent with activity of an uniporter carrier that facilitates the transport of anions through lipid membranes down the electrochemical gradient. There are no evidences of transport coupling with protons. The selectivity sequence of the prodigiosin inspired EH160 ionophore is formate > acetate > nitrate > chloride > bicarbonate. Sulfate, phosphate, aspartate, isothionate, and gluconate are not significantly transported by these anionophores. Protonation at acidic pH is important for the transport capacity of the anionophore. This prodigiosin derived ionophore induces anion transport in living cells. Its low toxicity and capacity to transport chloride and bicarbonate, when applied at low concentration, constitute a promising starting point for the development of drug candidates for CF therapy. European Union’s Horizon 2020 research and innovation programme under grant agreement No 667079 and Consejería de Educación de la Junta de Castilla y León (Project BU092U16). 2018-08-21T11:45:00Z 2018-08-21T11:45:00Z 2018-08 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 1663-9812 http://hdl.handle.net/10259/4874 10.3389/fphar.2018.00852 eng Frontiers in Pharmacology. 2018, V. 9, art. 852 https://doi.org/10.3389/fphar.2018.00852 info:eu-repo/grantAgreement/EC/H2020/667079 info:eu-repo/grantAgreement/JCyL/BU092U16 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Frontiers Media