Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein DeltaF508-CFTR.

A developing therapy of cystic fibrosis caused by the DeltaF508 mutation in CFTR employs correction of defective CFTR chloride channel gating by a 'potentiator' and of defective CFTR protein folding by a 'corrector'. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a-linker-CO(2)H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector 13 fragments (after cleavage) had low micromolar potency for restoration of DeltaF508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator 2 and corrector fragments 13, providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the DeltaF508 mutation.