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.
Mills
Aaron D
AD
Department of Chemistry, University of California, Davis, CA 95616, USA.
Yoo
Choong
C
Butler
Jeffrey D
JD
Yang
Baoxue
B
Verkman
A S
AS
Kurth
Mark J
MJ
D003550:Cystic Fibrosis / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists* / Q000378:metabolism; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D015640:Ion Channel Gating; D009154:Mutation; D017510:Protein Folding; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
D054852:Small Molecule Libraries; D013844:Thiazoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C008852:2-phenylglycine; D005998:Glycine