Specific rescue of cystic fibrosis transmembrane conductance regulator processing mutants using pharmacological chaperones.

Most mutants of the cystic fibrosis transmembrane conductance regulator (CFTR) that cause severe symptoms of cystic fibrosis do not reach the cell surface because they are defective in folding. Many CFTR folding mutants, however, including the DeltaF508 mutant found in more than 90% of cystic fibrosis patients, are potentially functional at the cell surface if they can be induced to fold correctly. In a previous study (Mol Pharm 2:407-413, 2005), we reported that a quinazoline derivative (CFcor-325) could rescue CFTR processing mutants. The corrector was not specific however, as it could also rescue a processing mutant of CFTR's sister protein, the multidrug resistance P-glycoprotein. The goal of this study was to test whether it was possible to specifically rescue CFTR processing mutants using a pharmacological chaperone. In this article, we report that two compounds, 4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol (CFpot-532) and 2-phenylamino-4-(4-ethylene-phenyl)-thiazole (corr-2b) could rescue CFTR processing mutants such as DeltaF508 CFTR but not a P-glycoprotein processing mutant. The compound CFpot-532 also acts as a potentiator of DeltaF508 CFTR channel activity. Therefore, the results suggest that the mechanism whereby CFpot-532 and corr-2b promote folding of CFTR processing mutants is through direct interaction with the CFTR mutant proteins. The compound CFpot-532 could be a particularly useful lead compound for treatment of cystic fibrosis because it is both a CFTR channel potentiator as well as a specific pharmacological chaperone.