Takahashi Azusa, Kondoh Masuo, Yagi Kiyohito
Department of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Yakugaku Zasshi. 2011;131(11):1583-7. doi: 10.1248/yakushi.131.1583.
The intercellular spaces between adjacent epithelial cells are sealed by tight junctions (TJs). Modulation of TJ-seal is a potent strategy for drug absorption. Claudin is a key structural and functional component of TJ-seal. Claudin comprises a tetra-transmembrane protein family consisting of more than 20 members, whose expression profiles and barrier-function differ among tissues. For instance, claudin-1 plays roles in the epidermal and mucosal barriers, and claudin-4 regulates the mucosal barrier. Claudin forms homo- and hetero-type TJ strands. Properties of TJ-seal are determined by combination of the claudin family members. Some claudin strands work as size-selective or charge-selective paracellular routes for solutes. Thus, claudin modulators will make it possible to deliver drugs in a solute- and tissue-specific manner. The C-terminal fragment of the Clostridium perfringens enterotoxin (C-CPE) is the most characterized claudin modulator. In this review, we describe potency of claudin-targeting mucosal absorption, and we mentioned development of a novel claudin modulator using C-CPE as a prototype.
相邻上皮细胞之间的细胞间隙由紧密连接(TJs)封闭。调节紧密连接的封闭作用是促进药物吸收的有效策略。Claudin是紧密连接封闭作用的关键结构和功能成分。Claudin是一个由20多个成员组成的四次跨膜蛋白家族,其表达谱和屏障功能在不同组织中有所不同。例如,Claudin-1在表皮和黏膜屏障中发挥作用,Claudin-4调节黏膜屏障。Claudin形成同型和异型紧密连接链。紧密连接封闭作用的特性由Claudin家族成员的组合决定。一些Claudin链作为溶质的大小选择性或电荷选择性细胞旁途径。因此,Claudin调节剂将使以溶质和组织特异性方式递送药物成为可能。产气荚膜梭菌肠毒素的C末端片段(C-CPE)是最具特征的Claudin调节剂。在这篇综述中,我们描述了靶向Claudin的黏膜吸收的效力,并提及了以C-CPE为原型开发新型Claudin调节剂的情况。