Developing ubiquitin chain- and target-specific deubiquitinase probes

摘要人去泛素酶（DUBs）的异常功能与许多人类疾病的发病机制有关，包括神经退行性疾病、癌症和病毒感染。人类dub正在成为药物干预的有希望的靶点。然而，缺乏对DUBs泛素链和靶蛋白特异性的了解阻碍了开发新疗法的进展。尽管已经发现无数的细胞蛋白质被泛素化，但DUB或DUB复合物负责许多这些蛋白质的去泛素化仍然未知。DUB探针可以识别DUB并研究其链和靶蛋白特异性，这是非常需要的。本应用程序的重点是开发一类新的DUB探针，该探针含有亲电基团，可以捕获含有催化半胱氨酸的DUB。这些探针将用于阐明人类DUBs的多泛素链特异性，并鉴定与帕金森病有关的泛素化蛋白-突触核蛋白特异性DUBs。负责-突触核蛋白去泛素化的DUB(s)将成为帕金森病（PD）治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): 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).