Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1

Shinya Tashiro, Jose Manuel Martinez Caaveiro, Makoto Nakakido, Aki Tanabe, Satoru Nagatoishi, Yasushi Tamura, Noriyuki Matsuda, Dali Liu, Quyen Q. Hoang, Kouhei Tsumoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

DJ-1 is a Parkinson's disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.

Original languageEnglish
Pages (from-to)2783-2793
Number of pages11
JournalACS Chemical Biology
Volume13
Issue number9
DOIs
Publication statusPublished - Sep 21 2018

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X Ray Crystallography
Oxidation-Reduction
Disease Progression
X ray crystallography
Assays
Proteins
In Vitro Techniques
Parkinson Disease Associated Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

Cite this

Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1. / Tashiro, Shinya; Martinez Caaveiro, Jose Manuel; Nakakido, Makoto; Tanabe, Aki; Nagatoishi, Satoru; Tamura, Yasushi; Matsuda, Noriyuki; Liu, Dali; Hoang, Quyen Q.; Tsumoto, Kouhei.

In: ACS Chemical Biology, Vol. 13, No. 9, 21.09.2018, p. 2783-2793.

Research output: Contribution to journalArticle

Tashiro, S, Martinez Caaveiro, JM, Nakakido, M, Tanabe, A, Nagatoishi, S, Tamura, Y, Matsuda, N, Liu, D, Hoang, QQ & Tsumoto, K 2018, 'Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1', ACS Chemical Biology, vol. 13, no. 9, pp. 2783-2793. https://doi.org/10.1021/acschembio.8b00701
Tashiro, Shinya ; Martinez Caaveiro, Jose Manuel ; Nakakido, Makoto ; Tanabe, Aki ; Nagatoishi, Satoru ; Tamura, Yasushi ; Matsuda, Noriyuki ; Liu, Dali ; Hoang, Quyen Q. ; Tsumoto, Kouhei. / Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1. In: ACS Chemical Biology. 2018 ; Vol. 13, No. 9. pp. 2783-2793.
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