Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine: A Candidate for Cystic Fibrosis Therapy

Claudia Cossu, Michele Fiore, Debora Baroni, Valeria Capurro, Emanuela Caci, Maria Garcia-Valverde, Roberto Quesada, Oscar Moran

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)852
JournalFrontiers in Pharmacology
Volume9
DOIs
Publication statusPublished - 2018

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Triazoles
Cystic Fibrosis
Anions
Chlorides
Prodigiosin
Bicarbonates
Cystic Fibrosis Transmembrane Conductance Regulator
formic acid
Ionophores
Unilamellar Liposomes
Inborn Genetic Diseases
Therapeutics
Membrane Lipids
Aspartic Acid
Nitrates
Sulfates
Protons
Acetates
Phosphates
Bacteria

Cite this

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; Garcia-Valverde, Maria; Quesada, Roberto; Moran, Oscar.

In: Frontiers in Pharmacology, Vol. 9, 2018, p. 852.

Research output: Contribution to journalArticle

Cossu, Claudia ; Fiore, Michele ; Baroni, Debora ; Capurro, Valeria ; Caci, Emanuela ; Garcia-Valverde, Maria ; Quesada, Roberto ; Moran, Oscar. / Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine : A Candidate for Cystic Fibrosis Therapy. In: Frontiers in Pharmacology. 2018 ; Vol. 9. pp. 852.
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