蛋白质溶解向奇美拉 (PROTAC) 通过血脑屏障进入大脑
1Tashima Laboratories of Arts and Sciences, 1239-5 Toriyama-cho, Kohoku-ku, Yokohama 222-0035, Japan.
Antibodies (Basel, Switzerland)
|July 25, 2023
概括
开发用于神经退行性疾病的药物是困难的,因为血脑屏障 (BBB). 本综述探讨了通过载体介导运输或受体介导转细胞因子传递的蛋白质分解向嵌合体 (PROTAC) 的使用,以有效进入大脑.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 药物运输 药物运输 药物运输
背景情况:
- 神经退行性疾病,如阿尔茨海默氏症,帕金森症和亨廷顿症,目前面临着重大药物开发挑战.
- 血脑屏障 (BBB) 限制了中枢神经系统 (CNS) 药物的药动力学传递.
- 不清楚的发病因子和复杂的进展机制使中枢神经系统疾病的药理学向复杂化.
研究的目的:
- 探索创新策略,在BBB中有效和选择性地提供中枢神经系统的药物.
- 引入向蛋白解的嵌合体 (PROTACs) 作为细胞内蛋白质降解的新疗法.
- 审查PROTACs的先进传递系统,以克服BBB无性并增强大脑向.
主要方法:
- 研究以载体为媒介的运输 (CMT) 对于向质子合有机阴子反载体的含N组的PROTACs.
- 检查受体介导细胞转移 (RMT) 的PROTAC-抗体结合物 (PACs),以促进BBB交叉.
- 评估大脑间歇液体内基于小分子的PROTACs细胞吸收的被动扩散.
主要成果:
- 通过ubiquitin-proteasome系统,PROTAC提供了一种新的方法来降解细胞内蛋白质.
- 目前的PROTAC传递方法 (基于或被动扩散) 缺乏细胞选择性,可能会导致目标外的效应.
- 像MDR1这样的流量输送器可以阻碍基于小分子的PROTACs进入大脑.
结论:
- CMT和RMT代表着有希望的智能交付系统,可以克服BBB的挑战.
- 使用CMT或RMT的PROTACs (例如PACs) 能够在脑内进行非侵入性输送.
- 针对性地在BBB提供PROTAC可以提高神经退行性疾病的治疗疗效.
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