基质和循环抑制剂的Oligonucleotide激活的Sirtuin 7的基质和循环抑制剂
Julie E Bolding1, Alexander L Nielsen1,2, Iben Jensen1
1Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark.
Angewandte Chemie (International ed. in English)
|October 24, 2023
概括
研究人员开发了新的化学工具来研究SIRT7,这是一个鲜为人知的Sirtuin酶. 他们发现了选择性抑制剂,可以稳定SIRT7并影响基因素乙化,进步了我们对这一重要的蛋白质的理解.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 酶学 是一种酶学.
背景情况:
- 赛尔图因 (SIRT) 是依赖NAD+的脱乙酶,调节各种生物过程.
- 由于有限的特定化学探测器,SIRT7,一个核和核细胞异型,对它的理解较少.
- 了解SIRT7的功能和调节对于其潜在的治疗应用至关重要.
研究的目的:
- 描述人类SIRT7.7的结构和酶特性.
- 开发新的化学工具,包括化试验,用于探测SIRT7活性和基质特异性.
- 为了识别和描述选择性SIRT7抑制剂.
主要方法:
- 人类SIRT7.7的表达和净化.
- 小角度X射线散射 (SAXS) 用于溶液中的结构分析.
- 开发一种化剂试验,以测量SIRT7活性.
- 为了发现抑制剂,mRNA显示库选.
- 细胞测试以评估抑制剂对SIRT7稳定性和基因素乙化的影响.
主要成果:
- 确定SIRT7是一种单体酶,溶液中的球体灵活性较低.
- 为SIRT7活性和抑制剂查建立了一种新的化剂测定方法.
- 确定了几种基于机制的和对SIRT7有选择性的de novo循环抑制剂.
- 这些抑制剂被证明可以稳定细胞中的SIRT7并增加H3K18乙化.
结论:
- 开发的化学工具允许对SIRT7.7进行具体的研究.
- 已识别的选择性SIRT7抑制剂为治疗干预提供了潜力.
- 抑制剂诱导的SIRT7稳定和改变的基因素乙化突显了SIRT7在细胞过程中的作用.
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