Issue 9, 2023

Click’n lock: rapid exchange between unsymmetric tetrazines and thiols for reversible, chemoselective functionalisation of biomolecules with on-demand bioorthogonal locking

Abstract

The late-stage functionalisation and diversification of complex structures including biomolecules is often achieved with the help of click chemistry. Besides employing irreversible click-like reactions, many synthetic applications benefit from reversible click reaction strategies, so called de-/trans-click approaches. Yet, the combination of both, reversible and irreversible click chemistry – while still respecting the stringent criteria of click transformations – remains so far elusive for modifications of biomolecular structures. Here, we report click’n lock as a concept that enables reversible click reactions and on-demand locking of chemical entities, thus switching from reversible to irreversible modifications of complex biomolecules. For this purpose, we employ the tetrazine–thiol exchange (TeTEx) reaction as a fully traceless click reaction with second order rate constants k2 higher than 2 M−1 s−1 within aqueous environments. Employing TeTEx as a reversible click reaction for the chemoselective modification of biomolecules is made possible by the use of 3,6-disubstituted 1,2,4,5-tetrazines bearing a single sulfide residue. The inherent reactivity of tetrazines towards inverse electron demand Diels–Alder (IEDDA) reactions allows to stabilize the clicked structure, switching from reversible to irreversible systems (click’n lock).

Graphical abstract: Click’n lock: rapid exchange between unsymmetric tetrazines and thiols for reversible, chemoselective functionalisation of biomolecules with on-demand bioorthogonal locking

Supplementary files

Article information

Article type
Paper
Submitted
04 mei 2023
Accepted
19 jul 2023
First published
20 jul 2023
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2023,4, 685-691

Click’n lock: rapid exchange between unsymmetric tetrazines and thiols for reversible, chemoselective functionalisation of biomolecules with on-demand bioorthogonal locking

K. Gavriel, D. C. A. van Doeselaar, D. W. T. Geers and K. Neumann, RSC Chem. Biol., 2023, 4, 685 DOI: 10.1039/D3CB00062A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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