Site-specific protein conjugation is a critical step in the generation of unique protein analogs for a range of basic research and therapeutic developments. Protein transformations must target a precise residue in the presence of a plethora of functional groups to obtain a well-characterized homogeneous product. Competing reactive residues on natural proteins render rapid and selective conjugation a challenging task. Organometallic reagents have recently emerged as a powerful strategy to achieve site-specific labeling of a diverse set of biopolymers, due to advances in water-soluble ligand design, high reaction rate, and selectivity. The thiophilic nature of various transition metals, especially soft metals, makes cysteine an ideal target for these reagents. The distinctive reactivity and selectivity of organometallic-based reactions, along with the unique reactivity and abundancy of cysteine within the human proteome, provide a powerful platform to modify native proteins in aqueous media. These reactions often provide the modified proteins with a stable linkage made from irreversible cross-coupling steps. Additionally, transition metal reagents have recently been applied for the decaging of cysteine residues in the context of chemical protein synthesis. Orthogonal cysteine protecting groups and functional tags are often necessary for the synthesis of challenging proteins, and organometallic reagents are powerful tools for selective, rapid, and water-compatible removal of those moieties. This review examines transition metal-based reactions of cysteine residues for the synthesis and modification of natural peptides and proteins.

中文翻译：

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过渡金属催化的位点半胱氨酸蛋白质多样化

特定部位的蛋白质结合是在一系列基础研究和治疗开发中产生独特蛋白质类似物的关键步骤。在存在大量官能团的情况下，蛋白质转化必须靶向精确的残基，才能获得特征明确的均质产品。天然蛋白质上竞争性的反应性残基使快速和选择性的缀合成为一项艰巨的任务。由于水溶性配体设计，高反应速率和选择性的进步，有机金属试剂最近已成为一种强大的策略，可以实现对多种生物聚合物进行定点标记。各种过渡金属（尤其是软金属）的亲硫性质使半胱氨酸成为这些试剂的理想靶标。有机金属基反应的独特反应性和选择性，以及人类蛋白质组中半胱氨酸的独特反应性和丰富性，为修饰水性介质中的天然蛋白质提供了强大的平台。这些反应通常使修饰的蛋白质具有由不可逆的交叉偶联步骤制成的稳定连接。另外，最近在化学蛋白质合成的背景下，过渡金属试剂已用于减少半胱氨酸残基。正交半胱氨酸保护基团和功能标签通常是合成具有挑战性的蛋白质所必需的，有机金属试剂是选择性，快速且与水相容地去除这些部分的有力工具。这项审查审查基于半胱氨​​酸残基的过渡金属为基础的合成和修饰天然肽和蛋白质的反应。