Developing ubiquitin chain- and target-specific deubiquitinase probes

描述（由申请人提供）：开发泛素链和靶蛋白特异性去泛素酶探针摘要人类去泛素酶（DUB）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目标。然而，缺乏对 DUB 的泛素链和靶蛋白特异性的了解阻碍了新型疗法的开发进展。尽管已发现大量细胞蛋白被泛素化，但负责许多这些蛋白质去泛素化的 DUB 或 DUB 复合物仍然未知。非常需要能够识别 DUB 并研究链和靶蛋白特异性的 DUB 探针。该应用的重点是开发一类新型 DUB 探针，该探针含有亲电子基团，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 DUB 的多聚泛素链特异性，并鉴定与帕金森病有关的泛素化蛋白 β-突触核蛋白特异性的 DUB。负责β-突触核蛋白去泛素化的 DUB 将作为帕金森病 (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).