A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation
A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation
复制标题
DOI：
10.1021/jacs.9b04744
复制
发表时间：
2019-08-14
影响因子：
15
通讯作者：
Toste, F. Dean
中科院分区：
文献类型：
--
作者：
Christian, Alec H.;Jia, Shang;Toste, F. Dean
我们报告了一种数据驱动的物理有机方法来开发具有可调加合物稳定性的新型蛋氨酸选择性生物共轭试剂。将由内在物理有机参数描述的结构特征的统计模型应用于预测模型的开发，并深入了解通过氧化还原激活化学标记（ReACT）对氧氮杂环丙烷和甲硫氨酸硫醚伴侣进行化学选择性偶联而形成的加合物稳定性的驱动特征。从这些分析中，揭示了硫酰亚胺稳定性和硫酰亚胺 nu (C=O) 伸缩频率之间的相关性。我们利用该分析所揭示的加合物稳定性的合理收益来实现用于肽装订的双氧氮杂环丙烷试剂的设计和合成。事实上，我们观察到，与未装订的同源物相比，通过 ReACT 装订甲硫氨酸形成的大环肽表现出更好的活细胞摄取，突出了这种独特的化学工具用于硫醚修饰的潜在效用。这项工作为更广泛地使用数据驱动方法进行生物共轭化学和其他化学生物学应用提供了一个模板。
We report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving the stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide nu (C=O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this unique chemical tool for thioether modification. This work provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications.