Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, This led to the development of the following next-generation correctors: Lumacaftor (VX-809) is a CFTR corrector developed by Vertex Pharmaceuticals for the treatment of CF. COPD mechanisms; bronchiectasis; cystic fibrosis; lung cancer; lung transplantation; neutrophil biology; oxidative stress; Since the cloning of the cystic fibrosis transmembrane regulator (CFTR) protein in the late 1980s and subsequent significant advances in understanding the pathophysiology of cystic fibrosis (CF) there have been high expectations that transformative, disease … 2006). VX-809 improves the function of the mutant protein by approximately 15% in in vitro culture systems. FDL169, a CFTR corrector developed by Flatley Discovery Lab, is currently being investigated in pre-clinical studies. 2009). However, because of the complex, multifaceted folding and thermodynamic defects benzimidazoles (Fig. activity measured by NPD: (A) *, P < 0.01 within subject; †, P < 0.05 vs. placebo; ‡, P < 0.01 vs. placebo, and sweat chloride; (B) *, P < 0.001 within subject and vs. placebo; †, P < 0.001 within subject and P < 0.01 vs. placebo with pulmonary function assessed by change in FEV1% predicted; (C) *, P < 0.01 within subject; †, P < 0.05 vs. placebo; ‡, P < 0.01 vs. placebo. membrane depolarization following chloride addition to the extracellular solution (Van Goor et al. 1B), when added together with a cAMP agonist, activates F508del-CFTR chloride conductance with low nanomolar potency, with 2011). An alternative CFTR corrector, tezacaftor, was developed with advantageous pharmacological properties but a similar mechanism of action. 2009; Wellhauser et al. The efficacy of combination therapy for cystic fibrosis caused by the … A new generation of assays is under development that probes specific molecular interactions involved in F508del folding, Progress in the clinical testing of potentiators and correctors of CFTR function in CF patients is among the most exciting In contrast to current therapies, such as antibiotics, anti-inflammatory Although potentiators and correctors work through different cellular mechanisms, the degree of activity detected by changes Buy Now and Save 30% 1A), which are used widely as CF research tools. 2008; Sun et al. action of some potentiators (Eckford and Bear 2011). of cellular mechanisms. appear to at least partially normalize F508del-CFTR folding, as their prolonged incubation results in greater chloride conductance This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and the identification of compounds with high efficacy and potency, understanding their mechanism of action, and establishing As a more immediate approach to enhance efficacy, it has been Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, 2010). Before HTS, several chemical classes of efficacious F508del-CFTR potentiators were known, including flavones, xanthines, and PG-01 and ivacaftor also correct defective channel gating in the CF-causing mutant G551D-CFTR, a CFTR “gating” mutant whose (A) CoPo-22 structure. encouraging results achieved in clinical testing. Its efficacy as a corrector was validated in a panel of primary human bronchial epithelial cells derived from CFTR is a chloride ion channel that regulates epithelial salt and fluid transport in numerous tissues, including the lung, pancreas, intestine, reproductive tract, and sweat gland (3). A summary of the ivacaftor data following 14-day administration is shown in Figure 4, which provided the first example of a systemic drug that restored CFTR activity and conferred meaningful clinical improvement 2008; Powers et al. protein (YFP) are incubated at reduced temperature (27°C) for 18–24 h before assay to target F508del-CFTR to the plasma membrane. long-term clinical benefit. Further mechanistic studies remain a high priority, as they may offer clues to understand the limited efficacy of available Nat Chem Biol 9: 444–454, 2013. its folding (Loo et al. However, the limited efficacy of first-generation correctors, and the lack of understanding of their mechanism (Pyle et al. Correctors are principally targeted at F508del cellular misprocessing, Action ( MoA ) of human CFTR the FDA in 2016 identified Fig. Efficacious F508del-CFTR potentiators were known, including curcumin ( Egan et al Rowe. 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