Tunable heteroaromatic azoline thioethers (HATs) for cysteine profiling

Abstract

Here we report a new series of hydrolytically stable chemotype heteroaromatic azoline thioethers (HATs) to achieve highly selective, rapid, and efficient covalent labeling of cysteine under physiological conditions. Although the resulting cysteine–azoline conjugate is stable, we highlight traceless decoupling of the conjugate to afford unmodified starting components in response to reducing conditions. We demonstrated that HAT probes reverse the reactivity of nucleophilic cysteine to electrophilic dehydroalanine (Dha) under mild basic conditions. We demonstrated the umpolung capability of HAT probes for the modification of cysteine on peptides and proteins with various nucleophiles. We demonstrated that HAT probes increase the mass sensitivity of the modified peptides and proteins by 100 fold as compared to the classical methods. Finally, we extended the application of HAT probes for specific modification of cysteines in a complex cell lysate mixture.

Graphical abstract: Tunable heteroaromatic azoline thioethers (HATs) for cysteine profiling

Supplementary files

Article information

Article type
Edge Article
Submitted
28 Jul 2021
Accepted
11 Dec 2021
First published
13 Dec 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022, Advance Article

Tunable heteroaromatic azoline thioethers (HATs) for cysteine profiling

K. C. Tang, S. M. Maddox, K. M. Backus and M. Raj, Chem. Sci., 2022, Advance Article , DOI: 10.1039/D1SC04139H

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