Issue 7, 2021

Deglycase-activity oriented screening to identify DJ-1 inhibitors

Abstract

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.

Graphical abstract: Deglycase-activity oriented screening to identify DJ-1 inhibitors

Supplementary files

Article information

Article type
Research Article
Submitted
24 Febr. 2021
Accepted
03 Maijs 2021
First published
02 Jūn. 2021

RSC Med. Chem., 2021,12, 1232-1238

Deglycase-activity oriented screening to identify DJ-1 inhibitors

I. Maksimovic, E. Finkin-Groner, Y. Fukase, Q. Zheng, S. Sun, M. Michino, D. J. Huggins, R. W. Myers and Y. David, RSC Med. Chem., 2021, 12, 1232 DOI: 10.1039/D1MD00062D

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