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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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Supplementary files

Article information


Submitted
09 Jan 2019
Accepted
18 Mar 2019
First published
18 Mar 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 4515-4522
Article type
Edge Article

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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