Abstract
The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.
Highlights
Thirty years after the identification and cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) [1], a transformational drug therapy for most people with cystic fibrosis (CF) received regulatory approval [2,3]
R This paper is part of a Supplement supported by The European Cystic Fibrosis Society (ECFS)
A bottleneck in the development of effective CFTR modulators has been a lack of insight into how CF mutations cause CFTR misfolding
Summary
Thirty years after the identification and cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) [1], a transformational drug therapy for most people with cystic fibrosis (CF) received regulatory approval [2,3]. The development of TrikaftaTM (elexacaftor-tezacaftor-ivacaftor) (Vertex Pharmaceuticals) is the culmination of great efforts to understand the structure of CFTR, its synthesis in epithelial cells, function as a ligand-gated anion. R This paper is part of a Supplement supported by The European Cystic Fibrosis Society (ECFS). There remains a pressing need to understand even better CFTR, its biosynthesis in cells, structure-function relationships and physiological roles. This knowledge will inform the development of generation small molecule CFTR modulators, leading to life-long personalised treatments for CF. Krainer and D.R.S. Ng et al / Journal of Cystic Fibrosis 19 (2020) S25–S32. For more comprehensive reviews of CFTR folding, function and pharmacology, we refer the Reader to [5,6,7,8,9]
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