Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a.
Eur Respir J
; 36(2): 311-22, 2010 Aug.
Article
in En
| MEDLINE
| ID: mdl-20110398
ABSTRACT
One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal alpha-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR. Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments. We report that GPact-11a 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr(+/+) but not cftr(-/-) mice; and 4) is selective for CFTR because its effect is inhibited by CFTR(inh)-172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Purines
/
Pyrimidines
/
Adenine
/
Cystic Fibrosis Transmembrane Conductance Regulator
Type of study:
Diagnostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur Respir J
Year:
2010
Document type:
Article