Glutathione mediates control of dual differential bio-orthogonal labelling of biomolecules

Frederik Peschke, Andrea Taladriz-Sender, Matthew J. Andrews, Allan J. B. Watson, Glenn A. Burley

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Abstract

Traditional approaches to bio-orthogonal reaction discovery have focused on developing reagent pairs that react with each other faster than they are metabolically degraded. Glutathione (GSH) is typically responsible for the deactivation of most bio-orthogonal reagents. Here we demonstrate that GSH promotes a Cu-catalysed (3+2) cycloaddition reaction between an ynamine and an azide. We show that GSH acts as a redox modulator to control the Cu oxidation state in these cycloadditions. Rate enhancement of this reaction is specific for ynamine substrates and is tuneable by the Cu:GSH ratio. This unique GSH-mediated reactivity gradient is then utilised in the dual sequential bio-orthogonal labelling of peptides and oligonucleotides via two distinct chemoselective (3+2) cycloadditions.

Original languageEnglish
Article numbere202313063
Number of pages11
JournalAngewandte Chemie International Edition
Volume62
Issue number50
Early online date13 Nov 2023
DOIs
Publication statusPublished - 11 Dec 2023

Keywords

  • bio-orthogonal chemistry
  • ligation
  • CuAAC
  • peptide
  • oligonucleotide

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