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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Imidazoles are Tunable Nucleofuges for Developing Tyrosine-Reactive Electrophiles
R Justin Grams1, Kun Yuan2, Michael W Founds1
1Department of Chemistry, University of Texas at Austin, 100 E 24th St, Texas, 78712, United States.
Chembiochem : a European Journal of Chemical Biology
|May 31, 2024
Summary
Imidazole sulfonyl and sulfonate reagents are valuable for protein bioconjugation. Arylsulfonyl imidazoles offer tunable electrophiles for targeting tyrosine and lysine sites, enabling development of specific covalent inhibitors.
Area of Science:
- Bioconjugation Chemistry
- Chemical Biology
Background:
- Imidazole-1-sulfonyl and -sulfonate (imidazylate) are established reagents in synthetic chemistry.
- Their application in protein bioconjugation remains underexplored despite imidazole prevalence in biological systems and pharmaceuticals.
Purpose of the Study:
- To explore the utility of imidazole-based electrophiles for protein bioconjugation.
- To develop novel probes for assessing protein ligandability and targeted covalent inhibition.
Main Methods:
- Synthesis of alkyne-modified sulfonyl- and sulfonate-imidazole probes.
- Investigation of imidazole electrophile reactivity and stability in biological contexts.
- Assessment of ligandability at tyrosine and lysine residues in cell proteomes.
Main Results:
- Alkylation of imidazole nitrogen yielded highly reactive but unstable sulfonyl-imidazolium electrophiles.
- Arylsulfonyl imidazoles demonstrated controlled reactivity as tempered electrophiles.
- Targeted covalent inhibitors were generated with reduced off-target activity.
Conclusions:
- Imidazole nucleofuges provide a tunable platform for creating sulfone-based electrophiles.
- These electrophiles can selectively bind functional tyrosine and lysine sites within the proteome.
- The findings support the development of targeted covalent drugs and chemical biology tools.
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