Novel short chain fatty acids restore chloride secretion in cystic fibrosis

Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective ΔF508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and α-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the ΔF508-CFTR defect. Pre-incubation (⩾6 h) of CF IB3-1 airway cells with ⩾1 mM ST7 or ST20 restored the ability of 100 μM forskolin to stimulate an 125I− efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl− channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the ΔF508 mutation.