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JCI Insight ; 3(14)2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30046015

RESUMO

SLC26A3 (downregulated in adenoma; DRA) is a Cl-/anion exchanger expressed in the luminal membrane of intestinal epithelial cells, where it facilitates electroneutral NaCl absorption. SLC26A3 loss of function in humans or mice causes chloride-losing diarrhea. Here, we identified slc26a3 inhibitors in a screen of 50,000 synthetic small molecules done in Fischer rat thyroid (FRT) cells coexpressing slc26a3 and a genetically encoded halide sensor. Structure-activity relationship studies were done on the most potent inhibitor classes identified in the screen: 4,8-dimethylcoumarins and acetamide-thioimidazoles. The dimethylcoumarin DRAinh-A250 fully and reversibly inhibited slc26a3-mediated Cl- exchange with HCO3-, I-, and thiocyanate (SCN-), with an IC50 of ~0.2 µM. DRAinh-A250 did not inhibit the homologous anion exchangers slc26a4 (pendrin) or slc26a6 (PAT-1), nor did it alter activity of other related proteins or intestinal ion channels. In mice, intraluminal DRAinh-A250 blocked fluid absorption in closed colonic loops but not in jejunal loops, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum. Oral DRAinh-A250 and tenapanor comparably reduced signs of constipation in loperamide-treated mice, with additive effects found on coadministration. DRAinh-A250 was also effective in loperamide-treated cystic fibrosis mice. These studies support a major role of slc26a3 in colonic fluid absorption and suggest the therapeutic utility of SLC26A3 inhibition in constipation.


Assuntos
Antiporters/farmacologia , Constipação Intestinal/tratamento farmacológico , Transportadores de Sulfato/antagonistas & inibidores , Transportadores de Sulfato/metabolismo , Animais , Antiporters/antagonistas & inibidores , Antiporters/química , Antiporters/genética , Antiporters/metabolismo , Antiportadores de Cloreto-Bicarbonato/farmacologia , Cloretos/metabolismo , Fibrose Cística , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Transporte de Íons , Loperamida/farmacologia , Camundongos , Ratos , Ratos Endogâmicos F344 , Trocador 3 de Sódio-Hidrogênio/farmacologia , Transportadores de Sulfato/genética , Transportadores de Sulfato/farmacologia
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