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

• Published in: Nature chemistry 2018-02, Vol.10 (2), p.205-211
• Main Authors: Bloom, Steven, Liu, Chun, Kölmel, Dominik K., Qiao, Jennifer X., Zhang, Yong, Poss, Michael A., Ewing, William R., MacMillan, David W. C.
• Format: Article
• Language: English
• Subjects: 639/638/403/933; 639/638/77/890; Adducts; Alkylation; Amino acids; Analytical Chemistry; Antibodies; Biochemistry; Carboxylates; Catalysis; Chemistry; Chemistry/Food Science; Conjugation; Decarboxylation; Electron transfer; Electron Transport; Inorganic Chemistry; Insulin; Insulin - chemical synthesis; Insulin - chemistry; Light; Models, Molecular; Molecular Structure; Organic Chemistry; Oxidation; Oxidation-Reduction; Peptides; Photoredox catalysis; Physical Chemistry; Proteins; Selectivity; Single electrons
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2888

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. Selectively targeting native amino acids for late-stage protein modification is a significant challenge, but now it has been shown that photoredox catalysis can be used to specifically target protein C-termini toward decarboxylative-alkylation with Michael acceptors. This technology harnesses innate differences in side-chain oxidation potentials to select between the various functional groups typical among proteins in order to form a single modified product.