Identification of novel CFTR activator and its application to inducing chloride transport at the mouse ocular surface (654.7)

Abstract

Impaired cystic fibrosis transmembrane conductance regulator (CFTR) function can lead to cystic fibrosis (CF). We developed a high‐throughput screen to identify small‐molecule activators of human airway epithelial Ca2+‐activated Cl‐ channels (CaCCs) for CF therapy. Unexpectedly, screening of ~110,000 synthetic small molecules revealed an amino‐carbonitrile‐pyrazole, Cact‐A1, that activated CFTR but not CaCC Cl‐ conductance. Cact‐A1 produced large and sustained CFTR Cl‐ currents in CFTR‐expressing Fisher rat thyroid (FRT) cells and in primary cultures of human bronchial epithelial (HBE) cells, without increasing intracellular cAMP and in the absence of a cAMP agonist. To investigate possible application of Cact‐A1 for dry eye, we studied that the effect of Cact‐A1 on the chloride transport at the mouse ocular surface in vivo. Open‐circuit potential differences across the ocular surface were measured in anesthetized mice. Application of Cact‐A1 on the mouse ocular surface induced further sustained hyperpolarization of ocular surface PD and it was inhibited by specific CFTR channel inhibitor CFTRinh‐172. The novel CFTR activator, Cact‐A1, identified in this study may be useful for drug therapy of dry eye.