Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation.
Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation.
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DOI：
10.1002/anie.202006260
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发表时间：
2020-12-21
期刊：
影响因子：
--
通讯作者：
Mitchell NJ
中科院分区：
文献类型：
--
作者：
Griffiths RC;Smith FR;Long JE;Williams HEL;Layfield R;Mitchell NJ
靶向典型氨基酸的位点选择性化学的发展使得能够将所需功能受控地安装到天然肽和蛋白质中。此类技术促进多肽缀合物的开发以推进治疗学、诊断学和基础科学。我们报告了一种通过自由基介导的脱卤功能化肽和蛋白质的通用和选择性方法。通过利用膦诱导的硒代半胱氨酸和半胱氨酸的C-Se和C-S键的均裂，我们分别证明了附加到持久性自由基陷阱的基团的位点选择性安装。该反应是快速的，操作简单，和化学选择性。所得的氨氧基连接基在各种条件下是稳定的，并且在低氧化态过渡金属的存在下可选择性裂解。我们已经探索了使用复杂的肽系统和重组表达的蛋白质的反应的全部范围。描述了通过捕获肽自由基物质来官能化肽和蛋白质。这种新颖且多用途的策略利用半胱氨酸和硒代胱氨酸残基的脱硫和脱硒过程，以使得能够位点选择性地安装附加到持久性自由基陷阱的广泛基团。
The development of site‐selective chemistry targeting the canonical amino acids enables the controlled installation of desired functionalities into native peptides and proteins. Such techniques facilitate the development of polypeptide conjugates to advance therapeutics, diagnostics, and fundamental science. We report a versatile and selective method to functionalize peptides and proteins through free‐radical‐mediated dechalcogenation. By exploiting phosphine‐induced homolysis of the C−Se and C−S bonds of selenocysteine and cysteine, respectively, we demonstrate the site‐selective installation of groups appended to a persistent radical trap. The reaction is rapid, operationally simple, and chemoselective. The resulting aminooxy linker is stable under a variety of conditions and selectively cleavable in the presence of a low‐oxidation‐state transition metal. We have explored the full scope of this reaction using complex peptide systems and a recombinantly expressed protein. Functionalization of peptides and proteins through the trapping of peptide radical species is described. This novel and versatile strategy exploits the process of desulfurization and deselenization of cysteine and selenocystine residues to enable the site‐selective installation of a broad range of groups appended to a persistent radical trap.
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