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Small molecule-facilitated anion transporters in cells for a novel therapeutic approach to cystic fibrosis
- Source :
- Br J Pharmacol, British journal of pharmacology 176 (2019): 1764–1779. doi:10.1111/bph.14649, info:cnr-pdr/source/autori:Fiore M, Cossu C, Capurro V, Picco C, Ludovico A, Mielczarek M, Carreira-Barral I, Caci E, Baroni D, Quesada R, Moran O/titolo:Small molecule-facilitated anion transporters in cells for a novel therapeutic approach to cystic fibrosis/doi:10.1111%2Fbph.14649/rivista:British journal of pharmacology/anno:2019/pagina_da:1764/pagina_a:1779/intervallo_pagine:1764–1779/volume:176, Repositorio Institucional de la Universidad de Burgos (RIUBU), instname
- Publication Year :
- 2018
-
Abstract
- BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CF transmembrane conductance regulator (CFTR) protein, a cAMP‐dependent anion channel involved in fluid transport across epithelium. Because small synthetic transmembrane anion transporters (anionophores) can replace the biological anion transport mechanisms, independent of genetic mutations in the CFTR, such anionophores are candidates as new potential treatments for CF. EXPERIMENTAL APPROACH: In order to assess their effects on cell physiology, we have analysed the transport properties of five anionophore compounds, three prodigiosines and two tambjamines. Chloride efflux was measured in large uni‐lamellar vesicles and in HEK293 cells with chloride‐sensitive electrodes. Iodide influx was evaluated in FRT cells transfected with iodide‐sensitive YFP. Transport of bicarbonate was assessed by changes of pH after a NH(4) (+) pre‐pulse using the BCECF fluorescent probe. Assays were also carried out in FRT cells permanently transfected with wild type and mutant human CFTR. KEY RESULTS: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores did not interfere with the activation of CFTR and did not modify the action of lumacaftor (a CFTR corrector) or ivacaftor (a CFTR potentiator). CONCLUSION AND IMPLICATIONS: These anionophores, at low concentrations, transported chloride and bicarbonate across cell membranes, without affecting CFTR function. They therefore provide promising starting points for the development of novel treatments for CF.
- Subjects :
- 0301 basic medicine
Cystic Fibrosis
Cell Survival
Bicarbonate
Chemistry, Organic
Cystic Fibrosis Transmembrane Conductance Regulator
CFTR POTENTIATOR
CHLORIDE TRANSPORT
IVACAFTOR
PROTEIN
PH
MEMBRANE
VX-809
DYSFUNCTION
LUMACAFTOR
EXPRESSION
Cell Line
Membrane Potentials
Cell membrane
Ivacaftor
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cricetulus
Chlorides
medicine
Animals
Humans
Drug Interactions
Ion transporter
Pharmacology
Ion Transport
Ionophores
Lumacaftor
Química orgánica
Hydrogen-Ion Concentration
Iodides
Fluid transport
Research Papers
Transmembrane protein
Rats
Bicarbonates
030104 developmental biology
medicine.anatomical_structure
chemistry
Biophysics
Efflux
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 14765381
- Volume :
- 176
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- British journal of pharmacology
- Accession number :
- edsair.doi.dedup.....0465458824ef4226390c15f11d1e3015