Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis


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Abstract

HighlightsCombining correctors that correct different folding defects improves efficacy.Complete F508del CFTR rescue likely requires full correction of NBD1.All classes of CF-causing mutations may benefit from correctors.F508del CFTR can be rescued from the ER by proteostasis regulators and amplifiers.The drug development pipeline contains promising CFTR corrector combinations.Pharmacological intervention to treat the lethal genetic disease cystic fibrosis has become reality, even for the severe, most common folding mutant F508del CFTR. CFTR defects range from absence of the protein, misfolding that leads to degradation rather than cell-surface localization (such as F508del), to functional chloride-channel defects on the cell surface. Corrector and potentiator drugs improve cell-surface location and channel activity, respectively, and combination therapy of two correctors and a potentiator have shown synergy. Several combinations are in the drug-development pipeline and although the primary defect is not repaired, rescue levels are reaching those resembling a cure for CF. Combination therapy with correctors may also improve functional CFTR mutants and benefit patients on potentiator therapy.

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