Abstract

Developing ubiquitin chain- and target protein-specific deubiquitinase probes Abstract Abnormal function of human deubiquitinases (DUBs) has been linked to the pathogenesis of a number of human diseases including neurodegenerative disorders, cancer and viral infection. Human DUBs are emerging as promising targets for pharmacological intervention. However, the lack of understanding of ubiquitin chain- and target protein-specificity of DUBs has hindered the progress in developing novel therapeutics. Although a myriad of cellular proteins have been found to be ubiquitinated, the DUBs or DUB complexes responsible for the deubiquitination of many of these proteins remain unknown. DUB probes that allow the identification of DUBs and the investigation of the chain and target protein specificity are highly desirable. This application focuses on the development a new class of DUB probes that contain an electrophilic group that can trap DUBs that contains a catalytic cysteine. The probes will be used to elucidate the polyubiquitin chain specificity of human DUBs and to identify DUBs specific for ubiquitinated protein ?-synuclein that is implicated in Parkinson's disease. The DUB(s) responsible for ?-synuclein deubiquitination will serve as a potential target for therapeutic intervention of Parkinson's disease (PD).

Public Health Relevance

Developing ubiquitin chain- and target protein-specific deubiquitinase probes Narrative Human deubiquitinases (DUB) have been linked to a number of diseases, including neurodegenerative disorders like Parkinson's disease. In order to exploit DUBs for therapeutic purposes, ubiquitin chain- and target protein-specific DUB probes are needed. This class of DUB probes is essential for understanding the DUB functions and for developing therapeutics that can specifically inhibit the human deubiquitinases implicated in neurodegeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS085509-02
Application #
8852722
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Sutherland, Margaret L
Project Start
2014-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716

  Publications

Li, Guorui; Yuan, Libo; Zhuang, Zhihao (2017) Chemical Synthesis of Activity-Based Diubiquitin Probes. Methods Mol Biol 1513:223-232
Ott, Christine A; Baljinnyam, Bolormaa; Zakharov, Alexey V et al. (2017) Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors. ACS Chem Biol 12:2399-2407
Yang, Kun; Li, Guorui; Gong, Ping et al. (2016) Chemical Protein Ubiquitylation with Preservation of the Native Cysteine Residues. Chembiochem 17:995-8