Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein ΔF508-CFTR

Aaron D. Mills, Choong Yoo, Jeffrey D. Butler, Baoxue Yang, A. S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


A developing therapy of cystic fibrosis caused by the ΔF508 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-CO2H 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 ΔF508-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 ΔF508 mutation.

Original languageEnglish (US)
Pages (from-to)87-91
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number1
StatePublished - Jan 1 2010


  • ΔF508-CFTR
  • Correctors
  • Cystic fibrosis transmembrane conductance regulator protein (CFTR)
  • Hybrids
  • Multi-ligand drug
  • Potentiators

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry


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