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

Dongkyu Jeon, Ikhyun Jun, Ho K. Lee, Jinhong Park, Bo Rahm Kim, Kunhi Ryu, Hongchul Yoon, Tae Im Kim, Wan Namkung

Research output: Contribution to journalArticlepeer-review

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 activ-ity. 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.

Original languageEnglish
Article number5206
JournalInternational journal of molecular sciences
Volume23
Issue number9
DOIs
Publication statusPublished - 2022 May 1

Bibliographical note

Funding Information:
This research was funded by National Research Foundation of Korea (NRF-2018R1A6A1A03023718, NRF-2020R1C1C1008332 and NRF-2021R1I1A1A01047951).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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