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Light-Activatable, 2,5-Disubstituted Tetrazoles for the Proteome-Wide Profiling of Aspartates and Glutamates in Living Bacteria

preprint
submitted on 11.12.2019 and posted on 18.12.2019 by Kathrin Bach, Bert L. H. Beerkens, Patrick R. A. Zanon, Stephan M. Hacker
Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, that do not rely on an enzymatic activity, have almost exclusively been developed to target cysteines. Expanding the scope to other amino acids would be largely facilitated by the ability to globally monitor their engagement by covalent inhibitors. Here, we present the use of light-activatable 2,5-disubstituted tetrazoles that allow quantifying 8971 aspartates and glutamates in the bacterial proteome with excellent selectivity. Using these probes, we competitively map the binding sites of two isoxazolium salts and introduce hydrazonyl chlorides as a new class of carboxylic acid-directed covalent protein ligands. As the probes are unreactive prior to activation, they allow global profiling even in living Gram-positive and Gram-negative bacteria. Taken together, this method to monitor aspartates and glutamates proteome-wide will lay the foundation to efficiently develop covalent inhibitors targeting these amino acids

Funding

Liebig Fellowship by the Fonds der Chemischen Industrie

Ph.D. fellowship by the Fonds der Chemischen Industrie

TUM Junior Fellow Fund

History

Email Address of Submitting Author

stephan.m.hacker@tum.de

Institution

Technical University of Munich

Country

Germany

ORCID For Submitting Author

0000-0001-5420-4824

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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