Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators

Abstract

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing.

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

“…Backbone RMSD (Å) differences between reported CFTR models. Models [1, 2, 3 and 12], [4][5][6] and [13][14], [7][8][9], [10][11] and [15][16] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 …”

“…Both strategies are best followed by the development of small molecules that would directly interact with the protein. 13 Rational discovery of such compounds is likely to be advanced by high resolution structures of CFTR and by an understanding of its folding and gating mechanisms.…”

Correctors of mutant CFTR enhance subcortical cAMP–PKA signaling through modulating ezrin phosphorylation and cytoskeleton organization

“…In the airway cells, the lack of a functional CFTR protein on the cell surface causes impaired mucociliary clearance and consequent opportunistic bacterial infections and progressive deterioration of lung function (Clunes and Boucher, 2011). The complexity of the defects of F508del CFTR trafficking and activation can be overcome by small-molecule modulators that can rescue the biosynthetic defect of F508del CFTR (termed 'correctors') and those that increase its regulated function once rescued to the cell surface (termed 'potentiators') (for reviews, see Rowe and Verkman, 2013;Zhang et al, 2012). However, the levels of plasma-membranerecovered F508del CFTR obtained by the correctors discovered until now, as well as the knowledge of their mechanisms of action, are still limited.…”

CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

“…However, these treatments target the consequences of CF rather than the actual cause of the disease (Ramsey et al, 2012). Novel therapeutic strategies are now aimed at correcting the anion channel function of CFTR by improving its gating activity or its plasma membrane insertion, which are both impaired by the mutations (Galietta, 2013;Rowe and Verkman, 2013). As highlighted in a recent National Heart, Lung, and Blood Institute workshop report ''emerging evidence suggests that CF lung disease begins in infancy and is initially 'silent' without overt signs or symptoms'' (Ramsey et al, 2012).…”