2025-10-23 愛媛大学
CL5Bは脳血管のClaudin-5に結合し、血液脳関門を短時間だけ開き、薬を脳内に届ける
<関連情報>
- https://www.ehime-u.ac.jp/data_relese/pr_20251023_pros/
- https://www.ehime-u.ac.jp/wp-content/uploads/2025/10/pr_20251023_pros.pdf
- https://www.sciencedirect.com/science/article/pii/S0168365925009289
クローディン5結合小分子は一時的に血液脳関門を開き、安全に脳への薬物送達を強化する Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery
Saito Inoue, Keisuke Shirakura, Atsuya Shirono, Jumpei Taguchi, Yoshiki Ikeda, Satomi Tomita, Risa Funatsu, Kosuke Muraoka, Yosuke Hashimoto, Keisuke Tachibana, Nobumasa Hino, Takefumi Doi, Yui Ikemi, Kazuto Nunomura, Bangzhong Lin, Shinsaku Nakagawa, Kazutake Tsujikawa, Shota Tanaka, Masanori Obana, Yasushi Fujio…Yoshiaki Okada
Journal of Controlled Release Available online: 11 October 2025
DOI:https://doi.org/10.1016/j.jconrel.2025.114314
Highlights
- A unique screening identified CL5B, a small molecule that binds to Claudin 5.
- CL5B enhanced endothelial permeability by altering Claudin 5 localization.
- CL5B transiently opened the blood-brain barrier for less than 30 min.
- CL5B delivered drugs up to 1.4 kDa specifically to the brain.
- CL5B-mediated brain delivery of methylscopolamine reduced seizure symptoms in mice.
Abstract
The blood–brain barrier (BBB) protects the brain from harmful substances, but it also limits drug delivery, hindering the treatment of brain diseases. Claudin 5, a tight junction protein in endothelial cells, plays a key role in maintaining the BBB integrity. Although modulation of Claudin 5 is a promising strategy for transiently opening the BBB, the currently available modulators often cause adverse effects due to strong or prolonged activity. Thus, we aimed to develop a moderate Claudin 5 modulator that enables safe and transient opening of the BBB. We identified a Claudin 5-binding small molecule (CL5B), capable of binding Claudin 5 via a high-throughput screening of 9600 compounds using a Claudin 5 antibody and proteoliposomes. CL5B increased endothelial permeability and tracer permeation across the endothelial monolayer by altering the localization of Claudin 5 without affecting its expression. In mice, CL5B transiently opened the BBB for less than 30 min, delivering drugs specifically to the brain. Notably, CL5B-facilitated delivery of methylscopolamine, a drug with limited brain penetration, alleviated seizure symptoms in a mouse epilepsy model. These findings demonstrate that CL5B is a safe BBB modulator that enhances brain drug delivery and holds therapeutic potential for brain diseases.
