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Title: Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule
Authors: Jia Liu
Hermann Bihler
Carlos M. Farinha
Nikhil T. Awatade
Ana M. Romão
Dayna Mercadante
Yi Cheng
Isaac Musisi
Walailak Jantarajit
Yiting Wang
Zhiwei Cai
Margarida D. Amaral
Martin Mense
David N. Sheppard
University of Bristol
Mahidol University
Faculdade de Ciências, Universidade de Lisboa
Cystic Fibrosis Foundation Therapeutics
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Apr-2018
Citation: British Journal of Pharmacology. Vol.175, No.7 (2018), 1017-1038
Abstract: © 2018 The British Pharmacological Society Background and Purpose: Rescue of F508del-cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the most common CF mutation, requires small molecules that overcome protein processing, stability and channel gating defects. Here, we investigate F508del-CFTR rescue by CFFT-004, a small molecule designed to independently correct protein processing and channel gating defects. Experimental Approach: Using CFTR-expressing recombinant cells and CF patient-derived bronchial epithelial cells, we studied CFTR expression by Western blotting and channel gating and stability with the patch-clamp and Ussing chamber techniques. Key Results: Chronic treatment with CFFT-004 improved modestly F508del-CFTR processing, but not its plasma membrane stability. By contrast, CFFT-004 rescued F508del-CFTR channel gating better than C18, an analogue of the clinically used CFTR corrector lumacaftor. Subsequent acute addition of CFFT-004, but not C18, potentiated F508del-CFTR channel gating. However, CFFT-004 was without effect on A561E-CFTR, a CF mutation with a comparable mechanism of CFTR dysfunction as F508del-CFTR. To investigate the mechanism of action of CFFT-004, we used F508del-CFTR revertant mutations. Potentiation by CFFT-004 was unaffected by revertant mutations, but correction was abolished by the revertant mutation G550E. These data suggest that correction, but not potentiation, by CFFT-004 might involve nucleotide-binding domain 1 of CFTR. Conclusions and Implications: CFFT-004 is a dual-acting small molecule with independent corrector and potentiator activities that partially rescues F508del-CFTR in recombinant cells and native airway epithelia. The limited efficacy and potency of CFFT-004 suggests that combinations of small molecules targeting different defects in F508del-CFTR might be a more effective therapeutic strategy than a single agent.
ISSN: 14765381
Appears in Collections:Scopus 2018

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