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 фев 2021
Accepted
03 май 2021
First published
02 июн 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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements