Merck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, USA.
Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, New Jersey 08543, USA.
Nat Chem. 2018 Feb;10(2):205-211. doi: 10.1038/nchem.2888. Epub 2017 Dec 4.
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可靠的选择性蛋白质修饰方法的需求，这种方法能够提供均一的加合物。虽然使用工程氨基酸的生物正交方法通常为选择性功能化的问题提供了一个优雅的解决方案，但使用天然氨基酸实现均一性仍然是一个挑战。在这里，我们探索可见光介导的单电子转移作为一种实现选择性和化学选择性生物偶联的机制。具体来说，我们展示了光氧化还原催化作为一种平台，其中内部与 C 末端羧酸之间的氧化还原电位差异可以被利用来专门获得 C 末端功能化。这种氧化还原电位门控技术适用于内源性肽，并已在胰岛素蛋白上成功证明。作为生物偶联的一种全新方法，这种方法为光氧化还原催化作为针对其他氧化还原活性侧链的通用平台的发展提供了蓝图，用于进行天然偶联。
