Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA; Division of Gastroenterology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Curr Opin Pharmacol. 2013 Dec;13(6):888-94. doi: 10.1016/j.coph.2013.08.005. Epub 2013 Aug 27.
Secretory diarrheas caused by bacterial and viral enterotoxins remain a significant cause of morbidity and mortality. Enterocyte Cl(-) channels represent an attractive class of targets for diarrhea therapy, as they are the final, rate-limiting step in enterotoxin-induced fluid secretion in the intestine. Activation of cyclic nucleotide and/or Ca(2+) signaling pathways in secretory diarrheas increases the conductance of Cl(-) channels at the enterocyte luminal membrane, which include the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca(2+)-activated Cl(-) channels (CaCCs). High-throughput screens have yielded several chemical classes of small molecule CFTR and CaCC inhibitors that show efficacy in animal models of diarrheas. Natural-product diarrhea remedies with Cl(-) channel inhibition activity have also been identified, with one product recently receiving FDA approval for HIV-associated diarrhea.
由细菌和病毒肠毒素引起的分泌性腹泻仍然是发病率和死亡率的重要原因。肠细胞 Cl(-) 通道代表了一类有吸引力的腹泻治疗靶点，因为它们是肠毒素诱导的肠道液体分泌的最终限速步骤。在分泌性腹泻中，环核苷酸和/或 Ca(2+) 信号通路的激活增加了肠细胞腔膜上 Cl(-) 通道的电导，其中包括囊性纤维化跨膜电导调节剂 (CFTR) 和 Ca(2+) 激活的 Cl(-) 通道 (CaCCs)。高通量筛选已经产生了几类小分子 CFTR 和 CaCC 抑制剂，它们在腹泻动物模型中显示出疗效。具有 Cl(-) 通道抑制活性的天然产物腹泻疗法也已被确定，其中一种产品最近获得 FDA 批准用于治疗 HIV 相关性腹泻。
