title: Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.
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.affiliation: Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, USA.
authors.forename: Fredrick
authors.initials: F
authors.lastname: Van Goor
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
authors.forename: Dong
authors.initials: D
authors.lastname: Cao
authors.forename: Jesús
authors.initials: J
authors.lastname: González
authors.forename: Sabine
authors.initials: S
authors.lastname: Hadida
authors.forename: Anna
authors.initials: A
authors.lastname: Hazlewood
authors.forename: John
authors.initials: J
authors.lastname: Joubran
authors.forename: Tom
authors.initials: T
authors.lastname: Knapp
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Makings
authors.forename: Mark
authors.initials: M
authors.lastname: Miller
authors.forename: Timothy
authors.initials: T
authors.lastname: Neuberger
authors.forename: Eric
authors.initials: E
authors.lastname: Olson
authors.forename: Victor
authors.initials: V
authors.lastname: Panchenko
authors.forename: James
authors.initials: J
authors.lastname: Rader
authors.forename: Ashvani
authors.initials: A
authors.lastname: Singh
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Stack
authors.forename: Roger
authors.initials: R
authors.lastname: Tung
authors.forename: Peter D J
authors.initials: PD
authors.lastname: Grootenhuis
authors.forename: Paul
authors.initials: P
authors.lastname: Negulescu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D003408:Cresols / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D011720:Pyrazoles / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D013961:Thyroid Gland / Q000502:physiology
chemical_list: D002712:Chlorides; D003408:Cresols; D011720:Pyrazoles; D011994:Recombinant Proteins; C535089:VRT 532; D019005:Cystic Fibrosis Transmembrane Conductance Regulator