The advent of antibody–drug conjugates as pharmaceuticals has fuelled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. Although bioorthogonal methods that use engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Here, we explore visible-light-mediated single-electron transfer as a mechanism towards enabling site- and chemoselective bioconjugation. Specifically, we demonstrate the use of photoredox catalysis as a platform to selectivity wherein the discrepancy in oxidation potentials between internal versus C-terminal carboxylates can be exploited towards obtaining C-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. As a fundamentally new approach to bioconjugation this methodology provides a blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation.

抗体-药物偶联物作为药物的出现推动了对提供均质加合物的可靠的定点选择性蛋白质修饰方法的需求。尽管使用工程氨基酸的生物正交方法通常为选择性功能化问题提供了一个优雅的解决方案，但是使用天然氨基酸实现均质性仍然是一个挑战。在这里，我们探索可见光介导的单电子转移，作为实现位点和化学选择性生物共轭的一种机制。具体来说，我们证明了使用光氧化还原催化作为选择性的平台，其中内部和C端羧酸盐之间的氧化电位差异可以用来专门获得C端功能化。这种氧化电位门控技术适用于内源肽，并已在蛋白质胰岛素上成功证明。作为一种基本的生物偶联新方法，该方法为光氧化还原催化的发展提供了一个蓝图，该氧化还原作为靶向其他氧化还原活性侧链进行天然偶联的通用平台。