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抑制14-3-3介导相互作用的二甲基合物的细胞内生成

Prakash Parvatkar¹, Nobuo Kato², Motonari Uesugi¹

¹Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University , Gokasho, Uji, Kyoto 611-0011, Japan.

Journal of the American Chemical Society

|December 4, 2015

概括

研究人员开发了一种新的方法, 在细胞内制造出抑制蛋白与蛋白相互作用 (PPI) 的大分子. 这种方法使用小的前体分子产生强大的细胞毒剂,为药物开发提供了新的策略.

科学领域:

生物化学
化学生物学
分子药理学

背景情况:

破坏细胞内蛋白质相互作用 (PPI) 对于理解细胞信号和开发新疗法至关重要.
设计细胞透的大分子以准广泛的PPI接口是一个重大挑战.
目前的策略往往难以有效地将大型功能化分子输入细胞.

研究的目的:

开发一种合理的策略来产生细胞透的大型分子以细胞内调节PPI.
使用细胞内氧基结合制造向14-3-3蛋白的两价抑制剂.
在细胞模型中评估生成的抑制剂的疗效和细胞毒性.

主要方法:

利用氧化物绑定从和素,一种二聚天然产物的细胞内结合物生成.
与含有化 (1) 和含有氨基氧 (2) 的细胞同时进行治疗,以形成细胞内双价抑制剂 (3).
评估了细胞内生成的结合物3与化学合成的3,并分析了14-3-3/cRaf相互作用的破坏.

主要成果:

通过氧基结合的细胞内生成3导致显著的细胞毒性.
化学合成的结合物3无法透细胞,没有细胞毒性.
与前体1或2不同,细胞内生成的结合物3选择性地破坏了内源14-3-3/cRaf相互作用.

结论:

通过氧化结合,细胞内产生大分子是抑制PPI的一种可行的策略.
这种方法克服了与预先合成的大分子相关的细胞透限制.
这项研究为开发针对PPI的治疗方法提供了一个有前途的新途径.

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