血脑屏障通过卡德林的调节机制
Elinaz Farokhi1,2, Ahmed L Alaofi1,3, Vivitri D Prasasty1,4
1Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS 66047, USA.
Exploration of drug science
|August 9, 2024
概括
阿拉-Asp-Thr循环5 (ADTC5) 和其衍生物结合了E-cadherin的EC1域,增加了血脑屏障 (BBB) 的多孔性. ADTC5显示了最高的亲和力,突出显示了Val6对BBB调制的重要性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- 乙素调解了血脑屏障 (BBB) 中的细胞-细胞粘附.
- 像ADTC5,ADTC7和ADTC9这样的被研究为BBB透性的潜在调节剂.
- 了解-E-cadherin相互作用对于开发BBB向策略至关重要.
研究的目的:
- 为了确定人类E-cadherin上ADTC5,ADTC7和ADTC9的结合部位.
- 阐明这些基调节BBB的机制.
- 为了比较ADTC5,ADTC7和ADTC9与E-cadherin的结合亲缘关系.
主要方法:
- 核磁共振 (NMR) 光谱 (2D H-N-HSQC) 与化学转移扰动 (CSP) 评估结合性质.
- 分子对接模拟以确定E-cadherin EC1域上的精确结合点.
- 对具有不同残留量的衍生物 (ADTC5,ADTC7,ADTC9) 的比较分析.
主要成果:
- 与ADTC7和ADTC9相比,ADTC5对E-cadherin EC1域的结合亲和度最高.
- 所有与EC1域内类似的疏水口袋结合的,与域交换相关.
- 结合ADTC5影响了EC1的C端尾的形状,与ADTC7的重叠比ADTC9更大.
结论:
- 类可以通过结合EC1域的域交换区域来抑制E-cadherin的跨相互作用.
- 这种抑制调节细胞间接口,导致BBB的细胞孔隙性增加.
- 在ADTC5中的Val6残留物对于高结合亲和度和有效的BBB调制至关重要.
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