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Issue 16, 2019
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Azabicyclic vinyl sulfones for residue-specific dual protein labelling

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Abstract

We have developed [2.2.1]azabicyclic vinyl sulfone reagents that simultaneously enable cysteine-selective protein modification and introduce a handle for further bioorthogonal ligation. The reaction is fast and selective for cysteine relative to other amino acids that have nucleophilic side-chains, and the formed products are stable in human plasma and are moderately resistant to retro Diels–Alder degradation reactions. A model biotinylated [2.2.1]azabicyclic vinyl sulfone reagent was shown to efficiently label two cysteine-tagged proteins, ubiquitin and C2Am, under mild conditions (1–5 equiv. of reagent in NaPi pH 7.0, room temperature, 30 min). The resulting thioether-linked conjugates were stable and retained the native activity of the proteins. Finally, the dienophile present in the azabicyclic moiety on a functionalised C2Am protein could be fluorescently labelled through an inverse electron demand Diels–Alder reaction in cells to allow selective apoptosis imaging. The combined advantages of directness, site-specificity and easy preparation mean [2.2.1]azabicyclic vinyl sulfones can be used for residue-specific dual protein labelling/construction strategies with minimal perturbation of native function based simply on the attachment of an [2.2.1]azabicyclic moiety to cysteine.

Graphical abstract: Azabicyclic vinyl sulfones for residue-specific dual protein labelling

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Publication details

The article was received on 09 Jan 2019, accepted on 18 Mar 2019 and first published on 18 Mar 2019


Article type: Edge Article
DOI: 10.1039/C9SC00125E
Chem. Sci., 2019,10, 4515-4522
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Azabicyclic vinyl sulfones for residue-specific dual protein labelling

    E. Gil de Montes, E. Jiménez-Moreno, B. L. Oliveira, C. D. Navo, P. M. S. D. Cal, G. Jiménez-Osés, I. Robina, A. J. Moreno-Vargas and G. J. L. Bernardes, Chem. Sci., 2019, 10, 4515
    DOI: 10.1039/C9SC00125E

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