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Published on: February 11, 2017
CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds
Emanuela Caci1, Chiara Folli, Olga Zegarra-Moran
1Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16148 Genova, Italy.
Abstract:
Activators of the CFTR Cl- channel may be useful for therapy of cystic fibrosis. Short-circuit current (Isc) measurements were done on human bronchial epithelial cells to characterize the best flavone and benzimidazolone CFTR activators identified by lead-based combinatorial synthesis and high-throughput screening. The 7,8-benzoflavone UCcf-029 was a potent activator of Cl- transport, with activating potency (<1 microM) being much better than other flavones, such as apigenin. The benzimidazolone UCcf-853 gave similar Isc but with lower potency (5-20 microM). In combination, the effect induced by maximal UCcf-029 and UCcf-029, UCcf-853, and apigenin increased strongly with increasing basal CFTR activity: for example, Kd for activation by UCcf-029 decreased from >5 to <0.4 microM with increasing basal Isc from approximately 4 microA/cm2 to approximately 12 microA/cm2. This dependence was confirmed in permeabilized Fischer rat thyroid cells stably expressing CFTR. Our results demonstrate efficacy of novel CFTR activators in bronchial epithelia and provide evidence that activating potency depends on basal CFTR activity.
Insights
Novel activators for the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel show promise for cystic fibrosis therapy. Their potency is enhanced by the cell
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene.
- CFTR Cl- channel activators are a potential therapeutic strategy for CF.
- Identifying potent and effective CFTR activators is crucial for developing new treatments.
Purpose of the Study:
- To characterize novel flavone and benzimidazolone CFTR activators.
- To evaluate the potency and efficacy of these activators in human bronchial epithelial cells.
- To investigate the influence of basal CFTR activity on activator potency.
Main Methods:
- Short-circuit current (Isc) measurements on human bronchial epithelial cells.
- High-throughput screening and lead-based combinatorial synthesis to identify activators.
- Experiments using permeabilized Fischer rat thyroid cells stably expressing CFTR.
Main Results:
- 7,8-benzoflavone UCcf-029 demonstrated potent CFTR activation (<1 microM), outperforming other flavones like apigenin.
- Benzimidazolone UCcf-853 showed similar effects but with lower potency (5-20 microM).
- The potency of UCcf-029 and UCcf-853 was significantly dependent on basal CFTR activity, with increased potency at higher basal activity.
Conclusions:
- Novel CFTR activators, UCcf-029 and UCcf-853, are effective in bronchial epithelia.
- The therapeutic efficacy of these activators is influenced by the cell's intrinsic CFTR activity.
- These findings support the development of CFTR activators tailored to individual patient's basal CFTR function.
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