Peptide inhibitors of chloride channels for treating secretory diarrhea

Morbidity and mortality associated with diarrheal diseases remain significant burdens on global health. In the developing world, the major sources of secretory diarrhea are infectious, including those caused by bacteria such as enterotoxic Escherichia coli, and viruses such as rotavirus. In many cases of secretory diarrhea, activation of pathways for cyclic nucleotides and/or Ca²⁺ signaling in the apical membrane of enterocytes increases the conductance of Cl^- channels at the enterocyte lumen-facing membrane. Those channels include the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca²⁺-activated Cl^- channel (CaCC). Inhibition of enterocyte Cl^- channels is an effective strategy for anti-secretory drug therapy. Small molecules and natural peptides with Cl^- channel inhibitory activity have shown efficacy in diarrhea models. Screening of natural peptides via the patch-clamp technique provides evidence that such channel inhibition by an extract of black tea may be responsible for its anti-diarrhea benefits.