Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice

• Published in: International journal of molecular sciences Vol. 23; no. 9; p. 5206
• Main Authors: Jeon, Dongkyu, Jun, Ikhyun, Lee, Ho K, Park, Jinhong, Kim, Bo-Rahm, Ryu, Kunhi, Yoon, Hongchul, Kim, Tae-Im, Namkung, Wan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.05.2022; MDPI
• Subjects: activator; Cact-3; CFTR; Channel gating; Chloride; Chloride transport; Chlorides; Chlorides - metabolism; Cornea; Cystic fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cytokines; dry eye disease; Dry Eye Syndromes - drug therapy; Epithelium; Eye diseases; HERG protein; High-throughput screening; Human subjects; Humans; Inflammation; Interferon; Interleukin 6; Ion Transport; Phenols; Potassium channels (voltage-gated); Scopolamine; Tumor necrosis factor-TNF; Tumor necrosis factor-α; dry eye disease; activator; scopolamine; CFTR; Cact-3
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23095206

Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.