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Development of non-invasive drug delivery system using claudin modulator

使用密蛋白调节剂开发非侵入性药物输送系统

基本信息

批准号：
21689006
负责人：
KONDOH Masuo
金额：
$ 16.47万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (A)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21689006/
关键词：
Claudin 非侵襲性投与細胞間隙 claudin 細胞間隙経路経皮吸収

项目摘要

Claudins (CL) are a family of tetra-transmembrane proteins that are the structural and functional components of tight junctions (TJ). CLs are promising targets for drug development because of their role in mucosal drug absorption and carcinogenesis. However, CL-targeted drug development has been delayed because CLs have low antigenicity and preparing CL proteins is difficult. We developed a novel CL binder by using the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) and a baculoviral display system. After screening CL binders from a C-CPE mutant-displaying library by using CL-displaying budded baculovirus (BV) we isolated a C-CPE mutant called m19, which bound to CL1, CL2, CL4 and CL5. A 3-dimensional analysis showed that m19 has a structural backbone similar to C-CPE. The charge density of the CL-binding domains of m19 and C-CPE differed, suggesting that electrostatic interactions may occur between m19 and CLs. Treatment of epithelial cells with m19 decreased the paracellular but not transcellular integrity, and m19 enhanced jejunal absorption. This is the first report of the isolation of a CL binder with broad specificity. These findings will contribute to future preparation of CL binders for CL-targeted drug development.

紧密连接蛋白（Claudins，CL）是一个四跨膜蛋白家族，是紧密连接（tightjunction，TJ）的结构和功能组分。由于CL在粘膜药物吸收和致癌中的作用，CL是药物开发的有希望的靶点。然而，CL靶向药物的开发已经被推迟，因为CL具有低抗原性并且制备CL蛋白是困难的。我们利用产气荚膜梭菌肠毒素（C-CPE）的C-末端片段和杆状病毒展示系统开发了一种新的CL结合剂。通过使用CL展示出芽杆状病毒（BV）从C-CPE突变体展示文库中筛选CL结合物，我们分离了一个C-CPE突变体，称为m19，其结合CL 1，CL 2，CL 4和CL 5。三维分析表明，m19具有类似于C-CPE的结构骨架。m19和C-CPE的CL结合结构域的电荷密度不同，表明m19和CL之间可能发生静电相互作用。用m19处理上皮细胞降低了细胞旁但不跨细胞的完整性，m19增强了空肠吸收。这是第一个报告的分离CL结合剂具有广泛的特异性。这些发现将有助于未来制备CL结合剂，用于CL靶向药物开发。