Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 140, Issue 3, Pages 273-283Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1016/j.jphs.2019.07.012
Keywords
Diarrhea; CFTR; Chalcone; AMPK; Chloride secretion
Categories
Funding
- Thailand Research Fund [DBG5980001, DBG6180029]
- Mahidol Medical Scholars Program
- Faculty of Science, Mahidol University
- Development and Promotion of Science and Technology Talents Project
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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 antisecretory action in vitro and in vivo by inhibiting CFTR Cl-channels. However, its CFTR inhibition potency is considerably low (IC50 > 10 mu M) 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 similar to 1.5 mu M. 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 beta (CaMKK beta). 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 CaMKK beta-AMPK pathways. (C) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.
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