使用无痕链接器在线粒体中输送和释放小分子探针
1Department of Biochemistry, Faculty of Medicine, §Department of Chemistry, Faculty of Arts and Science, and #Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
Journal of the American Chemical Society
|July 1, 2017
概括
研究人员开发了线粒体透 (MPP) 的可切割连接剂,以便在线粒体输送后释放治疗载荷. 这种方法克服了直接结合的活性损失,使线粒体药物有效向.
科学领域:
- 生物化学
- 分子生物学
- 提供药物
背景情况:
- 线粒体透 (MPP) 促进小分子的向输送到线粒体基质.
- 线粒体向对于开发新疗法和化学探针至关重要.
- 货物与MPP的直接共价结合可能会损害货物的生物活性.
研究的目的:
- 设计和评估可切割的链接器,以便在线粒体基质内从MPP无痕释放化学载荷.
- 为了优化链接器稳定性,在线粒体运输后有效释放货物.
- 通过直接的MPP结合来恢复负载分子的活性.
主要方法:
- 开发可切割的二硫化基连接剂用于MPP合物.
- 使用光报道系统调查二硫化物裂变动力学.
- 在细胞突变过程中评估结合体稳定性和线粒体内的载荷释放动力学.
- 评估释放的HSP90抑制剂 (Luminespib) 结合物的生物活性.
主要成果:
- 硫化物链接剂在细胞溶液中表现出足够的稳定性.
- 在线粒体局部化后24小时内实现了货物释放.
- 这种可切割链接系统成功地恢复了HSP90抑制剂Luminespib的活性.
- 结合剂诱导了与HSP90抑制相关的预期线粒体表型.
结论:
- 可切割的链接器可以从线粒体中的MPP释放无痕的化学载荷.
- 这种策略克服了直接结合的局限性,保护了货物活动.
- 开发的链接系统扩大了MPPs用于线粒体药物输送和化学生物学的实用性.
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