Department of Chemistry , University of California , Berkeley , California 94720 , United States.
Department of Chemistry , University of Utah , 315 South 1400 East , Salt Lake City , Utah 84112 , United States.
J Am Chem Soc. 2019 Aug 14;141(32):12657-12662. doi: 10.1021/jacs.9b04744. Epub 2019 Jul 30.
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 ν (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.
我们报告了一种数据驱动的、物理有机的方法，用于开发新的具有可调加合物稳定性的蛋氨酸选择性生物缀合试剂。通过 Redox Activated Chemical Tagging (ReACT)，应用统计模型对内在物理有机参数描述的结构特征进行了建模，以开发一个预测模型，并深入了解通过肟和蛋氨酸硫醚伙伴的化学选择性偶联形成的加合物稳定性的驱动因素。通过这些分析，揭示了亚磺酰亚胺稳定性与亚磺酰亚胺 ν(C═O)伸缩频率之间的相关性。我们利用这种分析揭示的加合物稳定性的合理增益，设计并合成了一种用于肽交联的双恶唑啉试剂。事实上，我们观察到通过 ReACT 在蛋氨酸处交联形成的大环肽在进入活细胞方面表现出改善的摄取，这突出了这种独特的化学工具在硫醚修饰方面的潜在用途。这项工作为更广泛地将数据驱动方法应用于生物缀合化学和其他化学生物学应用提供了模板。
