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Discovery of novel small molecule CFTR inhibitor through structural modification of compound from Thai plant: Mechanism and Anti‐diarrheal efficacy
Author(s) -
Sawasvirojwong Sutthipong,
Suksamrarn Sunit,
Chatsudthipong Varanuj,
Muanprasat Chatchai
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.884.1
Subject(s) - cystic fibrosis transmembrane conductance regulator , chloride channel , cholera toxin , secretion , forskolin , potency , cystic fibrosis , pharmacology , chemistry , cholera , ic50 , biochemistry , in vitro , biology , microbiology and biotechnology , medicine
Inhibition of Cystic fibrosis transmembrane conductance regulator (CFTR) is proposed as a promising therapeutic approach for cholera, one of the important health problems worldwide. To identify novel class of CFTR inhibitors, several natural compounds were structurally modified and tested for CFTR inhibitory effect in Fisher rat thyroid (FRT) cells stably expressing human CFTR. Among test compounds, compound 130 exhibited the highest potency (IC 50 ~10 μM). It inhibited CFTR‐mediated apical chloride current stimulated by forskolin, CPT‐cAMP and apigenin. CFTR inhibitory effect of compound 130 was reversible and not associated with cytotoxicity. Electrophysiological analysis indicated that compound 130 is a CFTR pore blocker. Similarly, compound 130 inhibited cAMP and cholera toxin‐induced chloride secretion across T84 cell monolayers without changing intracellular cAMP level. Interestingly, compound 130 inhibited calcium‐activated chloride channel with similar potency. Intraluminal injection of compound 130 blocked cholera toxin‐induced intestinal fluid secretion by ~80% in mouse closed‐loop models. In mouse open‐loop cholera models, oral administration of compound 130 prevented intestinal fluid secretion was by ~80%. This study reveals a new class of CFTR inhibitors, which holds the promise for treatment of infectious secretory diarrhea. This work was supported by the Thailand Research Fund and the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative.