细胞特异性降解希斯脱乙酶使用弹头化的蛋白解向奇美拉
Qi Jia1, Yue Zhang1, Feng Liu1
1State Key Laboratory of Chemo/Bio-Sensing and Chemometric, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082 P. R. China.
Analytical chemistry
|October 30, 2023
概括
这项研究引入了可激活的蛋白质解离向化马体 (PROTACs),用于向蛋白质降解. 通过将核弹头关在子里,这些PROTAC可以实现细胞特异性组胺脱乙酶 (HDAC) 降解,从而最大限度地减少副作用.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 针对蛋白质溶解的奇默体 (PROTACs) 提供了一种通过向蛋白质降解来开发药物的新方法.
- 目前的PROTACs可以由于非特异性降解和其弹头的性质导致系统性毒性.
研究的目的:
- 开发可激活的PROTACs用于细胞特异性降解基因组脱乙酶 (HDAC),以最大限度地减少副作用.
- 设计由特定的细胞条件或酶激活的PROTACs.
主要方法:
- 分子对接被用来识别HDAC抑制剂的关键向部分.
- 一种可激活酶的PROTAC通过将HDAC抑制剂的基组与NAD(P) H:子氧化还原酶1 (NQO1) 基质结合而设计.
- 一个对过氧化 (H2O2) 敏感的 PROTAC 被设计出来,以证明设计的通用性.
主要成果:
- 在NQO1的存在下,NQO1可激活的PROTAC被有效地转化为其活性形式.
- 在NQO1-阳性细胞中观察到HDAC6和抗增殖活性的特定降解.
- 响应H2O2的PROTAC在H2O2水平升高的细胞中显示出特定的HDAC6降解.
结论:
- 关闭对象蛋白的配体是一种可行的策略,用于开发可激活的PROTACs.
- 这种方法可以实现高度特定的蛋白质降解,减少非目标效应和最小的副作用.
- 可激活的PROTACs在向治疗开发中代表了一个有前途的新维度.
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