Opening CFTR in the Intestine: Flushing on Demand

new paper by Cil et al has described the discovery Aand characterization of a small molecule capable of opening the Cl channel cystic fibrosis transmembrane regulator (CFTR). CFTR accounts for the majority of salt and water secretion across mucosal surfaces and into the ducts of secretory glands, and it is important for mucosal hydration in the intestine, lung, and cornea. The new channel opener was identified from a library of 120,000 drug-like synthetic compounds by using a high-throughput, singlecell screen for agonists of Cl transport. It is a phenylquinoxalinone named CFTRactJ027. The investigators tested the idea that CFTRactJ027 may be applied clinically as a possible therapy for constipation. Constipation remains a significant and widespread clinical problem. The mainstays of management for decades have been various types of osmotic agents to hydrate the stool, or gut motility–stimulating drugs. More recently, new drugs have emerged that have sought to harness the natural flushing and lubrication mechanism in the intestine by promoting transepithelial fluid secretion. Prosecretory drugs currently approved include linaclotide, a peptide agonist of the guanylate cyclase C receptor, which activates CFTR. The drug also activates the other cyclic-nucleotide gated transporters responsible for the secretory response (basolateral Kþ channels and the Naþ/Kþ/2Clcotransporter NKCC1). Lubiprostone is a prostaglandin analog that is thought to increase intracellular cyclic adenosine monophosphate and activate CFTR along with the other cyclicnucleotide gated transporters in a similar way. Unlike linaclotidea and lubiprostone, however, CFTRactJ027 appears to act on CFTR alone, without affecting other transporters, and without affecting intracellular signaling intermediates such as the cyclic nucleotides. The benefit of direct action on the CFTR channel is clear: a defined mechanism of action, lower likelihood of side effects, and the possibility of mucosal targeting without systemic absorption. However, there are some disadvantages related to such a narrow scope of action. Cyclic guanosine monophosphate agonists such as linaclotide and plecanatide also modulate ascending sensory nerve pathways and colonic motor pathways to inhibit visceral pain proprioception and to promote motility. Both effects likely contribute to the clinical efficacy of these compounds in the treatment of patients with irritable bowel syndrome or other functional gastrointestinal disorders. Still, the article by Cil et al outlines a number of properties that make CFTRactJ027 a promising candidate for clinical applications. The investigators used a classic opioid mouse model of constipation and showed that CFTRactJ027 is both highly specific and effective at improving constipation. Strikingly, they showed that head-to-head, at least in this mouse model, CFTRactJ027 is more effective than