Related Experiment Video
Updated: Sep 23, 2025
Author Spotlight: Challenges in Developing Dry Eye Animal Models and Future Research Directions
Published on: February 9, 2024
Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice
Dongkyu Jeon1, Ikhyun Jun2, Ho K Lee1
1Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Korea.
Abstract:
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.
Insights
Researchers identified Cact-3, a novel activator of the cystic fibrosis transmembrane conductance regulator (CFTR), to treat dry eye disease. This compound stimulates chloride transport, increasing tear secretion and reducing ocular inflammation.
Area of Science:
- Ocular surface physiology
- Drug discovery and development
- Ion channel modulation
Background:
- The ocular epithelium expresses cystic fibrosis transmembrane conductance regulator (CFTR), crucial for chloride transport and fluid secretion.
- Dry eye disease is prevalent, with limited effective therapeutic strategies.
- Targeting CFTR offers a potential avenue for treating dry eye disease.
Purpose of the Study:
- To identify novel small molecules that activate CFTR and enhance ocular surface chloride secretion.
- To evaluate the therapeutic potential of identified CFTR activators for dry eye disease.
Main Methods:
- High-throughput screening of 50,000 small molecules to identify CFTR activators.
- Electrophysiological assessment of CFTR activity in cell lines (FRT) and primary human conjunctival epithelium.
- In vivo studies using mouse models of dry eye disease to assess tear secretion and ocular surface inflammation.
Main Results:
- Three novel CFTR activators were identified, with Cact-3 demonstrating potent and sustained activation of CFTR.
- Cact-3 significantly increased CFTR-mediated chloride transport in ocular tissues and stimulated tear secretion in mice.
- Cact-3 application reduced ocular surface damage and suppressed key proinflammatory factors in a dry eye disease model.
Conclusions:
- Cact-3 is a potent novel CFTR activator with significant therapeutic potential for dry eye disease.
- Cact-3's ability to enhance tear secretion and reduce inflammation makes it a promising candidate for further clinical development.
