从药解剂到弹头:NAD+ - 针对三醇作为基于机制的Sirtuin抑制剂
Florian Friedrich1, Marat Meleshin2, Niklas Papenkordt1
1Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
Angewandte Chemie (International ed. in English)
|October 30, 2025
概括
研究人员开发了新的Sirtuin Trapping Ligands (SirTraps),通过与NAD+辅因子形成稳定的添加物来抑制Sirtuins. 这种机制提供了一种新的,稳定的,可调节的方法,用于针对疾病中的这些酶.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 药用化学 医学化学
背景情况:
- 赛尔图因 (SIRT) 是NAD+依赖的酶,在生理和疾病途径中至关重要.
- 现有的向NAD+的SIRT抑制剂面临着不稳定性和非向效应等挑战.
研究的目的:
- 发现一种具有改进性质的新一类SIRT抑制剂.
- 阐明这些新型抑制剂的作用机制.
主要方法:
- 使用1,2,3-triazole化合物 (SirTraps) 进行基于机制的抑制.
- 通过X射线晶体学,动力学和质谱学来确认 adduct 形成.
- 在体外和细胞内研究,包括纳米BRET测定细胞向参与.
主要成果:
- SirTraps与NAD+形成停滞的三或三-ADP-ribose (ADPR) 添加物,在没有共价修饰的情况下抑制SIRT.
- 吸管形成涉及对NAD+的尼古丁胺 рибоoside部分进行核友攻击.
- SirTraps表现出强大的,同型选择性抑制,高稳定性,以及纳米分子细胞点参与.
结论:
- SirTraps代表了一种新的,稳定的,可调节的基于机制的SIRT抑制剂类.
- 这种抑制策略在SIRT之外有潜在的应用,包括其他依赖NAD+的酶.
- SirTraps为机制驱动的药物发现提供了一个有前途的平台.
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