ArticleThe Journal of pharmacology and experimental therapeutics2009
Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators.
Article in The Journal of pharmacology and experimental therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- G970R-CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect.Clinical and translational science · 2021Trial
- Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants.ACS pharmacology & translational science · 2024Review
- Laboratory Tools to Predict CFTR Modulator Therapy Effectiveness and to Monitor Disease Severity in Cystic Fibrosis.Journal of personalized medicine · 2024Review
- Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.International journal of molecular sciences · 2023Article
- Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.Journal of personalized medicine · 2022Review
- Theratyping of the Rare CFTR Variants E193K and R334W in Rectal Organoid-Derived Epithelial Monolayers.Journal of personalized medicine · 2022Article
- Anion Transport Using Core Functionalized Hyperbranched Polymers and Evidence of a Dense Packed Limit Based on Molecular Weight.Molecules (Basel, Switzerland) · 2021Article
- On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis.Frontiers in pharmacology · 2021Review
- Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.PLoS genetics · 2020Article
- Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.Scientific reports · 2019Article
- Inhibition of calpain 1 restores plasma membrane stability to pharmacologically rescued Phe508del-CFTR variant.The Journal of biological chemistry · 2019Article
- Matrine in association with FD‑2 stimulates F508del‑cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809.Molecular medicine reports · 2017Article
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific.Clinical and experimental gastroenterology · 2015Article
- Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors.Paediatric drugs · 2013Review
- Article
- Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.Journal of medicinal chemistry · 2011Article
- Emergent properties of proteostasis in managing cystic fibrosis.Cold Spring Harbor perspectives in biology · 2011Review
- Stimulation of murine intestinal secretion by daily genistein injections: gender-dependent differences.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2011Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The mutations G551D and G1349D, which affect the nucleotide-binding domains (NBDs) of CFTR protein, reduce channel activity. This defect can be corrected pharmacologically by small molecules called potentiators. CF mutations residing in the intracellular loops (ICLs), connecting the transmembrane segments of CFTR, may also reduce channel activity. We have investigated the extent of loss of function caused by ICL mutations and the sensitivity to pharmacological stimulation. We found that E193K and G970R (in ICL1 and ICL3, respectively) cause a severe loss of CFTR channel activity that can be rescued by the same potentiators that are effective on NBD mutations. We compared potency and efficacy of three different potentiators for E193K, G970R, and G551D. The 1,4-dihydropyridine felodipine and the phenylglycine PG-01 [2-[(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide] were strongly effective on the three CFTR mutants. The efficacy of sulfonamide SF-01 [6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid cycloheptylamide], another CFTR potentiator, was instead significantly lower than felodipine and PG-01 for the E193K and G970R mutations, and almost abolished for G551D. Furthermore, SF-01 modified the response of G551D and G970R to the other two potentiators, an effect that may be explained by an allosteric antagonistic effect. Our results indicate that CFTR potentiators correct the basic defect caused by CF mutations residing in different CFTR domains. However, there are differences among potentiators, with felodipine and PG-01 having a wider pharmacological activity, and SF-01 being more mutation specific. Our observations are useful in the prioritization and development of drugs targeting the CF basic defect.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.