The advent of antibody drug conjugates as pharmaceuticals has fueled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. While bioorthogonal methods that utilize engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Herein, 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 vs. <i>C</i>-terminal carboxylates can be exploited towards obtaining <i>C</i>-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. In all, this pioneering effort represents a fundamentally new approach to bioconjugation and provides an inaugural blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation.

Decarboxylative alkylation for site-selective bioconjugation of native proteins via oxidation potentials

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.