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).

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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.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Sutherland, Margaret L
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University of Delaware
Schools of Arts and Sciences
United States
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Yang, Kun; Li, Guorui; Gong, Ping et al. (2016) Chemical Protein Ubiquitylation with Preservation of the Native Cysteine Residues. Chembiochem 17:995-8