Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice
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...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/5206 |
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| author | Dongkyu Jeon Ikhyun Jun Ho K. Lee Jinhong Park Bo-Rahm Kim Kunhi Ryu Hongchul Yoon Tae-im Kim Wan Namkung |
| author_facet | Dongkyu Jeon Ikhyun Jun Ho K. Lee Jinhong Park Bo-Rahm Kim Kunhi Ryu Hongchul Yoon Tae-im Kim Wan Namkung |
| author_sort | Dongkyu Jeon |
| collection | DOAJ |
| description | 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<sup>−</sup> 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<sup>−</sup> 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. |
| first_indexed | 2024-03-10T04:03:01Z |
| format | Article |
| id | doaj.art-1129c437f63744e99929b1237afae56d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:03:01Z |
| publishDate | 2022-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1129c437f63744e99929b1237afae56d2023-11-23T08:28:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239520610.3390/ijms23095206Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye MiceDongkyu Jeon0Ikhyun Jun1Ho K. Lee2Jinhong Park3Bo-Rahm Kim4Kunhi Ryu5Hongchul Yoon6Tae-im Kim7Wan Namkung8Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, KoreaDepartment of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-Gu, Seoul 03722, KoreaYonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, KoreaYonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, KoreaDepartment of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-Gu, Seoul 03722, KoreaYonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, KoreaResearch Laboratories, ILDONG Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, KoreaDepartment of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-Gu, Seoul 03722, KoreaYonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, KoreaCystic 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<sup>−</sup> 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<sup>−</sup> 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.https://www.mdpi.com/1422-0067/23/9/5206CFTRactivatorCact-3dry eye diseasescopolamine |
| spellingShingle | Dongkyu Jeon Ikhyun Jun Ho K. Lee Jinhong Park Bo-Rahm Kim Kunhi Ryu Hongchul Yoon Tae-im Kim Wan Namkung Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice International Journal of Molecular Sciences CFTR activator Cact-3 dry eye disease scopolamine |
| title | Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice |
| title_full | Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice |
| title_fullStr | Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice |
| title_full_unstemmed | Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice |
| title_short | Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice |
| title_sort | novel cftr activator cact 3 ameliorates ocular surface dysfunctions in scopolamine induced dry eye mice |
| topic | CFTR activator Cact-3 dry eye disease scopolamine |
| url | https://www.mdpi.com/1422-0067/23/9/5206 |
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