Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.
Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.
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DOI：
10.1021/acs.bioconjchem.3c00322
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发表时间：
2023-09-20
影响因子：
4.7
通讯作者：
Baud, Matthias G. J.
中科院分区：
文献类型：
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作者：
Pichon, Maeva M.;Drelinkiewicz, Dawid;Lozano, David;Moraru, Ruxandra;Hayward, Laura J.;Jones, Megan;Mccoy, Michael A.;Allstrum-Graves, Samuel;Balourdas, Dimitrios-Ilias;Joerger, Andreas C.;Whitby, Richard J.;Goldup, Stephen M.;Wells, Neil;Langley, Graham J.;Herniman, Julie M.;Baud, Matthias G. J.
蛋白质的芳基化修饰对于开发具有改进性质的新型生物缀合物引起了广泛的关注。在这里，我们已经评估了2-磺酰基嘧啶作为共价弹头的温和，化学选择性，和无金属半胱氨酸S-芳基化。2-磺酰基嘧啶与半胱氨酸快速反应，在中性pH下产生稳定的S-杂芳基化加合物。微调杂环核心和环外离去基团允许可预测的体外SNAr反应性，覆盖>9个数量级。最后，我们实现了快速的化学和区域特异性芳基化的突变p53蛋白，并确认芳基化位点的蛋白质X-射线晶体学。因此，我们报告的第一个例子的蛋白质位点特异性S-芳基化碘芳香基序。总的来说，这项研究提供了迄今为止最全面的结构-反应性关系的杂芳基砜，并强调2-磺酰基嘧啶作为一种合成的易处理和蛋白质相容的共价基序，靶向反应性半胱氨酸，扩大武库的可调弹头现代共价配体的发现。
Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have 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 in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific 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.
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影响因子：
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作者：
Stephenson Clarke, Joseph R;Douglas, Leon R;Duriez, Patrick J;Balourdas, Dimitrios-Ilias;Joerger, Andreas C;Khadiullina, Raniya;Bulatov, Emil;Baud, Matthias G J
通讯作者：
Baud, Matthias G J
影响因子：
2.8
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通讯作者：
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作者：
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通讯作者：
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