Discovery of a novel chalcone derivative inhibiting CFTR chloride channel via AMPK activation and its anti-diarrheal application
| Autor: | Warinthorn Chavasiri, Chamnan Yibcharoenporn, Chatchai Muanprasat, Chanon Jakakul, Phakawat Chusuth, Thanyada Rungrotmongkol |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Diarrhea Male Chalcone Cystic Fibrosis Transmembrane Conductance Regulator Calcium-Calmodulin-Dependent Protein Kinase Kinase Pharmacology AMP-Activated Protein Kinases medicine.disease_cause Cell Line 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Chalcones Chlorides Chloride Channels medicine Animals Humans Protein kinase A Mice Inbred ICR Intestinal Secretions Kinase lcsh:RM1-950 Cholera toxin AMPK Biological Transport Epithelial Cells lcsh:Therapeutics. Pharmacology 030104 developmental biology chemistry Mechanism of action Chloride channel Molecular Medicine medicine.symptom 030217 neurology & neurosurgery Isoliquiritigenin |
| Zdroj: | Journal of Pharmacological Sciences, Vol 140, Iss 3, Pp 273-283 (2019) |
| ISSN: | 1347-8648 |
| Popis: | Secretory diarrhea is one of the most common causes of death world-wide especially in children under 5 years old. Isoliquiritigenin (ISLQ), a plant-derived chalcone, has previously been shown to exert anti-secretory action in vitro and in vivo by inhibiting CFTR Cl− channels. However, its CFTR inhibition potency is considerably low (IC50 > 10 μM) with unknown mechanism of action. This study aimed to identify novel chalcone derivatives with improved potency and explore their mechanism of action. Screening of 27 chalcone derivatives identified CHAL-025 as the most potent chalcone analog that reversibly inhibited CFTR-mediated Cl− secretion in T84 cells with an IC50 of ∼1.5 μM. As analyzed by electrophysiological and biochemical analyses, the mechanism of CFTR inhibition by CHAL-025 is through AMP-activated protein kinase (AMPK), a negative regulator of CFTR activity. Furthermore, Western blot analyses and molecular dynamics (MD) results suggest that CHAL-025 activates AMPK by binding at the allosteric site of an upstream kinase calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ). Interestingly, CHAL-025 inhibited both cholera toxin (CT) and bile acid-induced Cl− secretion in T84 cells and prevented CT-induced intestinal fluid secretion in mice. Therefore, CHAL-025 represents a promising anti-diarrheal agent that inhibits CFTR Cl− channel activity via CaMKKβ-AMPK pathways. Keywords: Diarrhea, CFTR, Chalcone, AMPK, Chloride secretion |
| Databáze: | OpenAIRE |
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