4.7 Article

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

Journal

Publisher

MDPI
DOI: 10.3390/ijms23095206

Keywords

CFTR; activator; Cact-3; dry eye disease; scopolamine

Funding

  1. [NRF-2018R1A6A1A03023718]
  2. [NRF-2020R1C1C1008332 andNRF-2021R1I1A1A01047951]

Ask authors/readers for more resources

The study identified Cact-3 as a novel CFTR activator that can stimulate chloride secretion in ocular epithelium and alleviate symptoms in a dry eye disease mouse model. This suggests that Cact-3 could be a potential drug candidate for the treatment of dry eye disease.
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-alpha]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)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available