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

Steven Bloom, Chun Liu, Dominik K. Kölmel, Jennifer X. Qiao, Yong Zhang, Michael A. Poss, William R. Ewing, David W.C. Macmillan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)205-211
Number of pages7
JournalNature chemistry
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2018

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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