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对 PARP-HPF1 相互作用抑制剂进行高通量选试验,以影响DNA损伤修复

Saurabh S Dhakar¹, Albert Galera-Prat¹, Lari Lehtiö²

¹Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.

Scientific reports

|February 16, 2024

概括

研究人员开发了一种新的测定方法,以寻找针对PARP1/2-HPF1相互作用的药物,这对于DNA修复至关重要. 这种方法确定了两个化合物,Dimethylacrylshikonin和Alkannin,作为潜在的抗癌剂.

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:

聚基聚合酶 (PARP1和PARP2) 是DNA修复中的关键酶,对于检测DNA损伤和启动修复途径至关重要.
PARP 抑制剂是已知的抗癌药物,在具有特定DNA修复缺陷的瘤中特别有效.
基因组PARylation Factor (HPF1) 与PARP1/2形成复合体,改变基质特异性,并在DNA损伤反应中发挥关键作用.

研究的目的:

开发一种高通量选 (HTS) 试验,以确定PARP1/2-HPF1相互作用的抑制剂.
为了验证该试验的稳定性和实用性,用于针对PARP-HPF1复合体的药物发现.

主要方法:

开发和优化基于Förster共振能量转移 (FRET) 的HTS试验,以监测PARP1/2-HPF1相互作用.
通过竞争性干扰来验证FRET信号和相互作用.
对抗PARP-HPF1复合物的抑制剂库的选.

主要成果:

基于FRET的测试被优化为信号检测,并被验证为稳定性和自动化.
两个化合物,Dimethylacrylshikonin和Alkannin,被确定为PARP1/2-HPF1与微分子功能的相互作用的抑制剂.
该试验在识别目标复合物的抑制剂方面表现可靠.

结论:

开发的FRET试验是一种可靠和可自动化的工具,用于发现PARP1/2-HPF1相互作用的抑制剂.
这种方法通过向PARP-HPF1复合体,为开发新的抗癌药物提供了一种新的策略.
已识别的化合物为进一步开发抗癌药物提供了一个起点.

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