TY - JOUR
T1 - Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion
AU - Ma, Tonghui
AU - Thiagarajah, Jay R.
AU - Yang, Hong
AU - Sonawane, Nitin D.
AU - Folli, Chiara
AU - Galietta, Luis J V
AU - Verkman, A. S.
PY - 2002/12
Y1 - 2002/12
N2 - Secretory diarrhea is the leading cause of infant death in developing countries and a major cause of morbidity in adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is required for fluid secretion in the intestine and airways and, when defective, causes the lethal genetic disease cystic fibrosis. We screened 50,000 chemically diverse compounds for inhibition of cAMP/flavone-stimulated Cl- transport in epithelial cells expressing CFTR. Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chemical class were identified. The most potent compound discovered by screening of structural analogs, CFTRinh-172, reversibly inhibited CFTR short-circuit current in less than 2 minutes in a voltage-independent manner with KI approximately 300 nM. CFTRinh-172 was nontoxic at high concentrations in cell culture and mouse models. At concentrations fully inhibiting CFTR, CFTRinh-172 did not prevent elevation of cellular cAMP or inhibit non-CFTR Cl- channels, multidrug resistance protein-1 (MDR-1), ATP-sensitive K+ channels, or a series of other transporters. A single intraperitoneal injection of CFTRinh-172 (250 μg/kg) in mice reduced by more than 90% cholera toxin-induced fluid secretion in the small intestine over 6 hours. Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas.
AB - Secretory diarrhea is the leading cause of infant death in developing countries and a major cause of morbidity in adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is required for fluid secretion in the intestine and airways and, when defective, causes the lethal genetic disease cystic fibrosis. We screened 50,000 chemically diverse compounds for inhibition of cAMP/flavone-stimulated Cl- transport in epithelial cells expressing CFTR. Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chemical class were identified. The most potent compound discovered by screening of structural analogs, CFTRinh-172, reversibly inhibited CFTR short-circuit current in less than 2 minutes in a voltage-independent manner with KI approximately 300 nM. CFTRinh-172 was nontoxic at high concentrations in cell culture and mouse models. At concentrations fully inhibiting CFTR, CFTRinh-172 did not prevent elevation of cellular cAMP or inhibit non-CFTR Cl- channels, multidrug resistance protein-1 (MDR-1), ATP-sensitive K+ channels, or a series of other transporters. A single intraperitoneal injection of CFTRinh-172 (250 μg/kg) in mice reduced by more than 90% cholera toxin-induced fluid secretion in the small intestine over 6 hours. Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas.
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U2 - 10.1172/JCI200216112
DO - 10.1172/JCI200216112
M3 - Article
C2 - 12464670
AN - SCOPUS:0036896008
VL - 110
SP - 1651
EP - 1658
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 11
ER -