Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation
Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation
复制标题
天然化学连接中肽基脯氨酰硫酯的内部激活
DOI：
10.1021/jacs.6b01202
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发表时间：
2016-04-13
影响因子：
15
通讯作者：
Dong, Suwei
中科院分区：
文献类型：
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作者：
Gui, Yue;Qiu, Lingqi;Dong, Suwei
与丙氨酰硫酯相比，脯氨酰硫酯在天然化学连接（NCL）中显示出显著较低的反应性。本报告描述了一种温和而有效的内部活化方案，肽基脯氨酰硫酯在NCL中不使用任何基于硫醇的添加剂，其中在C-末端脯氨酸上引入4-取代基，通过形成双环硫代内酯中间体显着提高脯氨酰硫酯的反应性。动力学数据表明，反应速率与丙氨酰硫酯的报道数据相当，并且机理研究表明，两个肽段的连接通过NCL样途径而不是直接氨解进行，这确保了各种氨基酸侧链的化学选择性和相容性。这种基于4-巯基脯氨酰基硫酯的方案还允许有效的一锅法连接-脱硫程序。该方法的实用性已在合成维尔姆斯肿瘤蛋白1的富含脯氨酸的区域中得到进一步证明。
Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) in comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol of peptidyl prolyl thioesters in NCL without using any thiol-based additives, where the introduction of a 4-mercaptan substituent on the C-terminal proline significantly improves the reactivity of prolyl thioesters via the formation of a bicyclic thiolactone intermediate. The kinetic data indicate that the reaction rate is comparable to that of the reported data of alanyl thioesters, and the mechanistic studies suggest that the ligation of two peptide segments proceeds through an NCL-like pathway instead of a direct aminolysis, which ensures the chemo-selectivity and compatibility of various amino acid side chains. This 4-mercaptoprolyl thioester-based protocol also allows an efficient one-pot ligation-desulfurization procedure. The utility of this method has been further demonstrated in the synthesis of a proline-rich region of Wilms tumor protein 1.