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Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.
Am J Physiol Lung Cell Mol Physiol 2006; 290(6):L1117-30AJ

Abstract

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl(-) channel. The most common mutation results in a deletion of phenylalanine at position 508 (DeltaF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of DeltaF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores DeltaF508-CFTR-mediated Cl(-) transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of DeltaF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.

Authors+Show Affiliations

Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16443646

Citation

Van Goor, Fredrick, et al. "Rescue of DeltaF508-CFTR Trafficking and Gating in Human Cystic Fibrosis Airway Primary Cultures By Small Molecules." American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 290, no. 6, 2006, pp. L1117-30.
Van Goor F, Straley KS, Cao D, et al. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol. 2006;290(6):L1117-30.
Van Goor, F., Straley, K. S., Cao, D., González, J., Hadida, S., Hazlewood, A., ... Negulescu, P. (2006). Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. American Journal of Physiology. Lung Cellular and Molecular Physiology, 290(6), pp. L1117-30.
Van Goor F, et al. Rescue of DeltaF508-CFTR Trafficking and Gating in Human Cystic Fibrosis Airway Primary Cultures By Small Molecules. Am J Physiol Lung Cell Mol Physiol. 2006;290(6):L1117-30. PubMed PMID: 16443646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. AU - Van Goor,Fredrick, AU - Straley,Kimberly S, AU - Cao,Dong, AU - González,Jesús, AU - Hadida,Sabine, AU - Hazlewood,Anna, AU - Joubran,John, AU - Knapp,Tom, AU - Makings,Lewis R, AU - Miller,Mark, AU - Neuberger,Timothy, AU - Olson,Eric, AU - Panchenko,Victor, AU - Rader,James, AU - Singh,Ashvani, AU - Stack,Jeffrey H, AU - Tung,Roger, AU - Grootenhuis,Peter D J, AU - Negulescu,Paul, Y1 - 2006/01/27/ PY - 2006/1/31/pubmed PY - 2006/8/12/medline PY - 2006/1/31/entrez SP - L1117 EP - 30 JF - American journal of physiology. Lung cellular and molecular physiology JO - Am. J. Physiol. Lung Cell Mol. Physiol. VL - 290 IS - 6 N2 - Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl(-) channel. The most common mutation results in a deletion of phenylalanine at position 508 (DeltaF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of DeltaF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores DeltaF508-CFTR-mediated Cl(-) transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of DeltaF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF. SN - 1040-0605 UR - https://www.unboundmedicine.com/medline/citation/16443646/Rescue_of_DeltaF508_CFTR_trafficking_and_gating_in_human_cystic_fibrosis_airway_primary_cultures_by_small_molecules_ L2 - http://www.physiology.org/doi/full/10.1152/ajplung.00169.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -