![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication March 2, 2006.
Revised April 12, 2006.
Accepted for publication April 19, 2006.
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 including the 
F508 mutant found in more than 90% of cystic fibrosis patients however, are potentially functional at the cell surface if they can be induced to fold correctly. In a previous study (Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2005) Mol. Pharm. 2, 407-413), 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. Here, 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 F508 CFTR but not a P-glycoprotein processing mutant. The compound CFpot-532 also acts as a potentiator of F508 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 activator as well as a specific pharmacological chaperone.
Key words:
Ion transporters (SERCA, Na/K ATPase, CFTR), MDR/p-Glycoprotein, Mutagenesis/Chimeric approaches
This article has been cited by other articles:
|
|
 |
|
  D. E. Grove, M. F.N. Rosser, H. Y. Ren, A. P. Naren, and D. M. Cyr Mechanisms for Rescue of Correctable Folding Defects in CFTR{Delta}F508 Mol. Biol. Cell, September 15, 2009; 20(18): 4059 - 4069. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wellhauser, P. K. Chiaw, S. Pasyk, C. Li, M. Ramjeesingh, and C. E. Bear A Small-Molecule Modulator Interacts Directly with {Delta}Phe508-CFTR to Modify Its ATPase Activity and Conformational Stability Mol. Pharmacol., June 1, 2009; 75(6): 1430 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Smith, A. A. C. Reed, N. Y. Loh, R. V. Thakker, and J. D. Lippiat Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure Am J Physiol Renal Physiol, February 1, 2009; 296(2): F390 - F397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Loo, M. C. Bartlett, and D. M. Clarke Arginines in the First Transmembrane Segment Promote Maturation of a P-glycoprotein Processing Mutant by Hydrogen Bond Interactions with Tyrosines in Transmembrane Segment 11 J. Biol. Chem., September 5, 2008; 283(36): 24860 - 24870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Norez, M. Pasetto, M. C. Dechecchi, E. Barison, C. Anselmi, A. Tamanini, F. Quiri, L. Cattel, P. Rizzotti, F. Dosio, et al. Chemical conjugation of {Delta}F508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl- channel functions Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L336 - L347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Norez, F. Bilan, A. Kitzis, Y. Mettey, and F. Becq Proteasome-Dependent Pharmacological Rescue of Cystic Fibrosis Transmembrane Conductance Regulator Revealed by Mutation of Glycine 622 J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 89 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, T. W. Loo, M. C. Bartlett, and D. M. Clarke Correctors Promote Maturation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-processing Mutants by Binding to the Protein J. Biol. Chem., November 16, 2007; 282(46): 33247 - 33251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Conn, A. Ulloa-Aguirre, J. Ito, and J. A. Janovick G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo Pharmacol. Rev., September 1, 2007; 59(3): 225 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. S. Sabeva, E. J. Rouse, and G. A. Graf Defects in the Leptin Axis Reduce Abundance of the ABCG5-ABCG8 Sterol Transporter in Liver J. Biol. Chem., August 3, 2007; 282(31): 22397 - 22405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, T. W. Loo, M. C. Bartlett, and D. M. Clarke Modulating the Folding of P-Glycoprotein and Cystic Fibrosis Transmembrane Conductance Regulator Truncation Mutants with Pharmacological Chaperones Mol. Pharmacol., March 1, 2007; 71(3): 751 - 758. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
