Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy

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 t...

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Autores: Cossu, Claudia, Fiore, Michele, Baroni, Debora, Capurro, Valeria, Caci, Emanuela, García Valverde, María, Quesada Pato, Roberto, Moran, Óscar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Burgos (UBU)
Repositorio:Repositorio Institucional de la Universidad de Burgos (RIUBU)
OAI Identifier:oai:riubu.ubu.es:10259/4874
Acceso en línea:http://hdl.handle.net/10259/4874
Access Level:acceso abierto
Palabra clave:cystic fibrosis
ionophore
ion transport
phospholipid vesicles
prodigiosin derivatives
Química orgánica
Chemistry, Organic
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spelling Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapyCossu, ClaudiaFiore, MicheleBaroni, DeboraCapurro, ValeriaCaci, EmanuelaGarcía Valverde, MaríaQuesada Pato, RobertoMoran, Óscarcystic fibrosisionophoreion transportphospholipid vesiclesprodigiosin derivativesQuímica orgánicaChemistry, OrganicCystic 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).Frontiers Media201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10259/4874reponame:Repositorio Institucional de la Universidad de Burgos (RIUBU)instname:Universidad de Burgos (UBU)InglésFrontiers in Pharmacology. 2018, V. 9, art. 852https://doi.org/10.3389/fphar.2018.00852info:eu-repo/grantAgreement/EC/H2020/667079info:eu-repo/grantAgreement/JCyL/BU092U16/Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:riubu.ubu.es:10259/48742026-05-28T07:56:11Z
dc.title.none.fl_str_mv Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
title Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
spellingShingle Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
Cossu, Claudia
cystic fibrosis
ionophore
ion transport
phospholipid vesicles
prodigiosin derivatives
Química orgánica
Chemistry, Organic
title_short Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
title_full Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
title_fullStr Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
title_full_unstemmed Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
title_sort Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy
dc.creator.none.fl_str_mv Cossu, Claudia
Fiore, Michele
Baroni, Debora
Capurro, Valeria
Caci, Emanuela
García Valverde, María
Quesada Pato, Roberto
Moran, Óscar
author Cossu, Claudia
author_facet Cossu, Claudia
Fiore, Michele
Baroni, Debora
Capurro, Valeria
Caci, Emanuela
García Valverde, María
Quesada Pato, Roberto
Moran, Óscar
author_role author
author2 Fiore, Michele
Baroni, Debora
Capurro, Valeria
Caci, Emanuela
García Valverde, María
Quesada Pato, Roberto
Moran, Óscar
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cystic fibrosis
ionophore
ion transport
phospholipid vesicles
prodigiosin derivatives
Química orgánica
Chemistry, Organic
topic cystic fibrosis
ionophore
ion transport
phospholipid vesicles
prodigiosin derivatives
Química orgánica
Chemistry, Organic
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10259/4874
url http://hdl.handle.net/10259/4874
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv 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/
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositorio Institucional de la Universidad de Burgos (RIUBU)
instname:Universidad de Burgos (UBU)
instname_str Universidad de Burgos (UBU)
reponame_str Repositorio Institucional de la Universidad de Burgos (RIUBU)
collection Repositorio Institucional de la Universidad de Burgos (RIUBU)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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