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超叠:混合增强结合和强制α-螺旋形态用于组合图书馆的亲和选择

Pramod M Sabale¹, Mateusz Imiołek¹, Pierre Raia¹

¹Faculty of Science, NCCR Chemical Biology, University of Geneva, 30 Quai Ernest Ansermet, CH-1205 Geneva, Switzerland.

Journal of the American Chemical Society

|November 5, 2021

概括

这项研究引入了一种使用PNA-联体和核组合制造合的新方法. 这种方法可以对蛋白质与蛋白质相互作用的选进行组合性图库.

科学领域:

医学化学
生物化学
合成生物学

背景情况:

拼接为稳定α-螺旋形态提供了一个有希望的策略,克服了针对蛋白质-蛋白质相互作用 (PPI) 的局限性.
由于制备的复杂性,目前对合成库的选方法没有得到广泛采用.
在药物发现过程中,开发高效的方法来生成结构受约束的库至关重要.

研究的目的:

使用核酸 (PNA) 结合物和核基驱动组装合成的新策略.
为了使片的组合结合和构造约束成为阿尔法螺旋.
将这种方法应用于针对PPI目标的基于亲和性的选.

主要方法:

通过核基驱动组装促进短PNA-联体的混合.
使用原生化学结合片的组合结合.
结合与固定目标蛋白的亲和选择.
使用质谱测量来确定最佳结合剂.

主要成果:

一个结反应成功生成了100个接的库.
该方法有效地将制成阿尔法螺旋形状.
对p53/MDM2相互作用标进行了强效结合剂的鉴定.
该方法在选聚焦库中表现出成功的应用.

结论:

报告的策略提供了一个高效和多功能平台,用于生成受构造约束的库.
核基驱动组合和本地化学结合为合成和选提供了强大的组合.
这种方法有助于发现针对具有挑战性的蛋白质-蛋白质相互作用的新疗法.

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