Stimulation of Wild-Type, F508del- and G551D-CFTR Chloride Channels by Non-Toxic Modified pyrrolo[2,3-b]pyrazine Derivatives
| Autor: | Mathilde Jollivet, Arnaud Billet, Frédéric Becq, Luc Dannhoffer, Christelle Faveau, Patricia Melin-Heschel |
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| Přispěvatelé: | Institut de physiologie et biologie cellulaires (IPBC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Pathology
medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Mutant [SDV.BC]Life Sciences [q-bio]/Cellular Biology Cystic fibrosis cystic fibrosis ion transport 03 medical and health sciences 0302 clinical medicine medicine Pharmacology (medical) CFTR Cytotoxicity 030304 developmental biology Original Research Pharmacology 0303 health sciences biology business.industry Chinese hamster ovary cell lcsh:RM1-950 Wild type activator and inhibitor Transfection respiratory system medicine.disease Molecular biology Cystic fibrosis transmembrane conductance regulator epithelial cells 3. Good health respiratory tract diseases lcsh:Therapeutics. Pharmacology 030220 oncology & carcinogenesis Chloride channel biology.protein [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology business |
| Zdroj: | Frontiers in Pharmacology Frontiers in Pharmacology, Frontiers, 2011, 2, ⟨10.3389/fphar.2011.00048⟩ Frontiers in Pharmacology, Vol 2 (2011) |
| ISSN: | 1663-9812 |
| DOI: | 10.3389/fphar.2011.00048 |
| Popis: | International audience; Cystic fibrosis (CF) is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs due to abnormal function of cystic fibrosis transmembrane conductance regulator (CFTR) protein. We recently identified a family of CFTR activators, which contains the hit: RP107 [7-n-butyl-6-(4-hydroxyphenyl)[5H]pyrrolo[2,3-b]pyrazine]. Here, we further evaluated the effect of the chemical modifications of the RP107-OH radical on CFTR activation. The replacement of the OH radical by a fluorine atom at position 2 (RP193) or 4 (RP185) significantly decreased the toxicity of the compounds without altering the ability to activate CFTR, especially for RP193. The nontoxic compound RP193 has no effect on cAMP production but stimulates the channel activity of wild-type CFTR in stably transfected CHO cells, in human bronchial epithelial NuLi-1 cells, and in primary culture of human bronchial epithelial cells (HBEC). Wholecell and single patch-clamp recordings showed that RP193 induced a linear, time-and voltage-independent current, which was fully inhibited by two different and selective CFTR inhibitors (CFTRinh-172 and GP inh 5a). Moreover, RP193 stimulates CFTR in temperaturerescued CuFi-1 (F508del/F508del) HBEC and in CHO cells stably expressing G551D-CFTR. This study shows that it is feasible to reduce cytotoxicity of chemical compounds without affecting their potency to activate CFTR and to rescue the class 2 F508del-CFTR and class 3 G551D-CFTR CF mutant activities. |
| Databáze: | OpenAIRE |
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