由形形状驱动的大宏环中的膜透性
Justin H Faris1, Emel Adaligil2, Nataliya Popovych3
1Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States.
Journal of the American Chemical Society
|February 8, 2024
概括
研究人员优化了细胞膜透性的宏环,这是针对细胞内蛋白质的一个关键挑战. 这项工作增强了针对具有挑战性的药物发现的类库的设计.
科学领域:
- 医学化学
- 药物发现
- 化学生物学
背景情况:
- 开发超越小分子的配体对于调节具有挑战性的蛋白质标至关重要.
- 来自mRNA显示的宏环具有较高的亲和力,但具有较差的膜透性,限制其用于细胞外向.
研究的目的:
- 研究宏环的被动膜透性.
- 改善用于细胞内的宏环库的设计.
主要方法:
- 通过 thioether 循环模式选了超过 200 个宏循环 10-mers.
- 在循环-混合基架中确定了最佳的性.
- 分析了影响透性的形状变化.
主要成果:
- 确定了在乙烯循环的10-mer支架中增强透性的最佳脂性范围.
- 证明骨干变换可以保持透性.
- 由于单个氨基酸的变化,在高度透的支架上观察到一种新的形折叠,隔离脊柱NH组.
结论:
- 物理化学知识可以指导透性宏环mRNA显示库的设计.
- 这种方法可以使图书馆偏向设计上的透性.
- 在传统的药物化空间之外,
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