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

Nature Chemistry volume 10, pages 205211 (2018) | Download Citation

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.

  • Compound

    riboflavin tetrabutyrate

  • Compound

    lumiflavin

  • Compound

    diethyl ethylidenemalonate

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Acknowledgements

The authors acknowledge financial support provided by the NIHGMS (R01 01GM093213-04) and gifts from Merck and BMS. D.K.K. acknowledges the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (KO 4867/2-1). The authors thank T. Muir, Z. Brown, R. Thompson and members of the Muir Laboratory for their advice and analytical support. The authors also thank I. Pelczer and K. Conover for assistance with NMR spectroscopy.

Author information

Author notes

    • Steven Bloom
    •  & Chun Liu

    These authors contributed equally to this work.

Affiliations

  1. Merck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, USA

    • Steven Bloom
    • , Chun Liu
    • , Dominik K. Kölmel
    • , Jennifer X. Qiao
    • , Yong Zhang
    • , Michael A. Poss
    • , William R. Ewing
    •  & David W. C. MacMillan
  2. Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, New Jersey 08543, USA

    • Jennifer X. Qiao
    • , Yong Zhang
    • , Michael A. Poss
    •  & William R. Ewing

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Contributions

S.B., C.L. and D.K.K. performed and analysed the experiments. S.B., C.L., D.K.K. and D.W.C.M. designed the experiments and prepared this manuscript. J.X.Q., Y.Z., M.A.P. and W.R.E. provided discussions. J.X.Q. assisted with peptide synthesis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David W. C. MacMillan.

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DOI

https://doi.org/10.1038/nchem.2888

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