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Deglycase-activity oriented screening to identify DJ-1 inhibitors
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-6-2 , DOI: 10.1039/d1md00062d
Igor Maksimovic 1, 2 , Efrat Finkin-Groner 3 , Yoshiyuki Fukase 3 , Qingfei Zheng 2 , Shan Sun 3 , Mayako Michino 3 , David J Huggins 3, 4 , Robert W Myers 3 , Yael David 1, 2, 4, 5
Affiliation  

The oncoprotein and Parkinson's disease-associated enzyme DJ-1/PARK7 has emerged as a promiscuous deglycase that can remove methylglyoxal-induced glycation adducts from both proteins and nucleotides. However, dissecting its structural and enzymatic functions remains a challenge due to the lack of potent, specific, and pharmacokinetically stable inhibitors targeting its catalytic site (including Cys106). To evaluate potential drug-like leads against DJ-1, we leveraged its deglycase activity in an enzyme-coupled, fluorescence lactate-detection assay based on the recent understanding of its deglycation mechanism. In addition, we developed assays to directly evaluate DJ-1's esterase activity using both colorimetric and fluorescent substrates. The resulting optimized assay was used to evaluate a library of potential reversible and irreversible DJ-1 inhibitors. The deglycase activity-oriented screening strategy described herein establishes a new platform for the discovery of potential anti-cancer drugs.

中文翻译:

以去糖酶活性为导向的筛选以鉴定 DJ-1 抑制剂

癌蛋白和帕金森病相关酶 DJ-1/PARK7 已成为一种混杂的去糖酶,可以从蛋白质和核苷酸中去除甲基乙二醛诱导的糖基化加合物。然而,由于缺乏针对其催化位点(包括 Cys106)的有效、特异性和药代动力学稳定的抑制剂,剖析其结构和酶功能仍然是一项挑战。为了评估针对 DJ-1 的潜在药物样线索,我们基于最近对其去糖化机制的了解,在酶偶联荧光乳酸检测测定中利用其去糖化酶活性。此外,我们开发了使用比色和荧光底物直接评估 DJ-1 酯酶活性的检测方法。由此产生的优化测定用于评估潜在的可逆和不可逆 DJ-1 抑制剂库。本文描述的以脱糖酶活性为导向的筛选策略为发现潜在的抗癌药物建立了一个新平台。
更新日期:2021-06-02
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