硫素启发的N-phosphonopiperidones作为选择性的共价DPP8和DPP9抑制剂
Leonard Sewald1, Werner W A Tabak1, Lorenz Fehr1
1Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
Nature communications
|April 3, 2025
概括
研究人员开发了针对二二酶 (DPP) 8和9 (DPP8 / 9) 的新型共价抑制剂. 微调化学弹头的微调.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 酶学 是一种酶学.
背景情况:
- 共价化学探针具有独特的药理性质,并通过化学蛋白质平台促进化合物分析.
- 电友性"弹头"对于系统的共价化学探测器发现至关重要.
- 开发针对二乙酶 (DPP8) 和二乙酶 (DPP9) 的全蛋白体选择性共价探针仍然具有挑战性.
研究的目的:
- 探索天然产品硫素作为开发DPP8/9抑制剂的起点.
- 为了产生苏尔福斯灵感衍生物,提高DPP8/9抑制功效和选择性.
- 用新型共价探针证实DPP8/9在细胞中的参与.
主要方法:
- 探索天然产品硫素,一种已知的DPP4抑制剂.
- 合成苏尔福斯胺启发的N-phosphonopiperidone衍生物.
- 评估DPP8/9.9的抑制功效,全蛋白质组选择性和细胞参与.
主要成果:
- 生成的N-phosphonopiperidone衍生物具有增强的DPP8/9抑制功效.
- 对于开发的DPP8/9抑制剂,获得了改善的全蛋白质组选择性.
- 在蜂模型中确认了DPP8/9的目标参与.
结论:
- 弹头离开组的结构微调是实现目标选择性的可行策略.
- 这种方法对于开发像DPP这样的外蛋白酶的选择性共价探针是有效的.
- 开发的化合物代表了研究DPP8/9功能的有希望的工具.
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