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宏环被一个thioether-bipyridyl单元封闭,使细胞膜具有透性

Hongxue Chen¹, Takayuki Katoh¹, Hiroaki Suga¹

¹Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

ACS bio & med chem Au

|October 25, 2023

概括

使用疏水性双 (BPy) 单元对的宏环化增强了细胞膜的透性和稳定性. 这种新的方法,结合随机非标准集成发现 (RaPID),有效地向像BRD4.4这样的细胞内蛋白质.

科学领域:

生物化学生物化学
分子生物学分子生物学
药用化学医学化学

背景情况:

针对细胞内分子的类疗法需要高效的膜透性.
传统的多化膜透模式面临着蛋白酶脆弱性和内体逃逸的挑战.

研究的目的:

开发一种使用疏水性双 (BPy) 单元进行的宏环化新策略,以提高膜的透性和蛋白质溶解稳定性.
通过随机非标准集成发现 (RaPID) 平台使用BPy宏循环系统发现有力的细胞内结合剂.

主要方法:

模型宏环的化学合成由一个 thioether-BPy 单元关闭.
使用 RaPID 系统与甲基-BPy (ClMeBPy) 启动器用于针对 BRD4 原体的类库合成.
在实验室中对已识别的BPy宏循环的解离常数和细胞膜透性的表征.

主要成果:

由乙烯-BPy单元封闭的宏环显示出比非宏环对应物具有40倍更好的膜透性.
通过RaPID识别的BPy宏循环对BRD4表现出单位纳米分子亲和力,与R9和Tat相比,具有优越的膜透性.
标有蛋白酶标动机的BPy宏循环在细胞内显示了适度的BRD4降解.

结论:

用像BPy这样的疏水性单元进行类宏环化,显著提高了细胞膜的透性和蛋白质溶解稳定性.
拉皮德系统和BPy宏循环的结合为开发透细胞,向细胞内蛋白质的化物提供了一个有前途的战略.
这种方法有可能为各种细胞内标发现新疗法.

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