| Autor: |
Maëva Pichon, Dawid Drelinkiewicz, David Lozano, Ruxandra Moraru, Laura Hayward, Megan Jones, Michael Mccoy, Samuel Allstrum-Graves, Dimitrios-Ilias Balourdas, Andreas Joerger, Richard Whitby, Stephen Goldup, Neil Wells, Graham Langley, Julie Herniman, Matthias Baud |
| Rok vydání: |
2023 |
| Popis: |
Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have systematically evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective and metal free cysteine S-arylation. 2-sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity with model tripeptide glutathione in vitro, covering 9 orders of magnitude. We achieved extremely fast chemo- and regio- specific arylation of a mutant p53 protein, and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones, and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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