Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
Angew Chem Int Ed Engl. 2019 Apr 8;58(16):5282-5285. doi: 10.1002/anie.201814645. Epub 2019 Mar 12.
The methylation states of Lys and Arg represent a particularly challenging set of targets to distinguish selectively in water using synthetic receptors. To date, trimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lys and Arg that can be recognized selectively. Here, we report the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using a biased dynamic combinatorial chemistry (DCC) library to generate a receptor mimicking the 5-sided box-like shape of Rme2 reader proteins, a feature that has been hypothesized to impart selectivity. Additionally, we synthesized a thioether-linked analogue of the resulting receptor to provide a novel scaffold with maintained selectivity but greater stability. This work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.
赖氨酸和精氨酸的甲基化状态代表了一组特别具有挑战性的目标，使用合成受体在水中选择性地区分它们。迄今为止，三甲基赖氨酸（Kme3）是赖氨酸和精氨酸的八种可能甲基化状态中唯一可以选择性识别的翻译后修饰（PTM）。在这里，我们报告了第一个能够选择性识别不对称二甲基精氨酸（Rme2a）的合成受体。这是通过使用偏向动态组合化学（DCC）文库来实现的，该文库生成了一种受体，模拟了 Rme2 读取蛋白的 5 边盒形状，据推测这种形状赋予了选择性。此外，我们合成了所得受体的硫醚连接类似物，提供了一种具有保持选择性但更高稳定性的新型支架。这项工作引入了基于水溶液中亲水客体的细微差异来实现选择性的策略。
