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LRRK2 dimerization and therapeutic evaluation

LRRK2二聚化和治疗评估

基本信息

批准号：
9243623
负责人：
WANLI W SMITH
金额：
$ 21.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243623
关键词：
Affect Age Attenuated Biochemical Biological Brain Cell physiology Cells Chemicals Clinical Computer Assisted Computer Simulation Cytoplasmic Protein Deposition Development Dimerization Disease Disease Progression Drosophila genus Drug Design Event Future GTP Binding Goals Guanosine Triphosphate Phosphohydrolases Homologous Gene Human In Vitro Intervention LRRK2 gene Lead Lewy Bodies Link Modality Modeling Molecular Molecular Weight Mutation Nerve Degeneration Neurodegenerative Disorders Parkinson Disease Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Pilot Projects Play Population Proteins Reporting Research Roentgen Rays Role Site Structure Structure-Activity Relationship Substantia nigra structure Symptoms Testing Therapeutic Agents Therapeutic Intervention Therapeutic Studies Toxic effect base dimer dopaminergic neuron drug development drug discovery in vivo inhibitor/antagonist insight kinase inhibitor motor symptom mutant neuron loss neuronal growth new therapeutic target novel novel therapeutic intervention novel therapeutics prevent small molecule symptom treatment targeted treatment therapeutic evaluation tool

项目摘要

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Currently, there is no proven neuroprotective therapy for PD and approaches for the identification of novel treatments are underdeveloped. Mutations in Leucine-rich repeat kinase-2 (LRRK2) are the most common known cause of Parkinson's disease (PD). LRRK2 is a large cytoplasmic protein (2527 aa) and contains both GTPase and kinase activities. Although efforts have been spent on developing LRRK2-targeted therapies, so far none of these are being utilized in a clinical setting. Thus, exploration and identification of novel therapeutic site(s) in the large LRRK2 protein may provide novel avenues for PD intervention. Recent studies suggest that the LRRK2 GTPase domain plays an important role in LRRK2 functions. PD-linked LRRK2 mutations within the GTPase domain alter either GTP binding or GTPase activity. Abolishing GTP binding by genetic alteration or pharmacological inhibition attenuates LRRK2 kinase activity and protects against neurodegeneration. Notably, the crystal structure of the LRRK2 GTPase domain shows it to be a dimer and biological studies suggest that LRRK2 may need to dimerize to act as a functional protein involved in cellular processes and neuronal growth. In this proposal, we propose to target the LRRK2 GTPase domain and identify dimerization inhibitors using computer-aided drug design (CADD) and biological screens. We will test the hypothesis that blocking LRRK2 dimerization by small molecules can attenuate LRRK2-induced neurodegeneration in LRRK2 cell and Drosophila models. These studies will validate whether blocking LRRK2 GTPase domain dimerization is a viable target for the development of novel therapeutic agents for PD intervention, and provide novel pharmacological tools for LRRK2-linked pathogenesis and therapeutic studies.

帕金森病（PD）是最常见的神经退行性疾病之一，其特征是选择性多巴胺能神经元的丧失和路易体的存在。目前尚无经过证实的神经保护作用 PD 的治疗方法和识别新疗法的方法尚不成熟。突变在富含亮氨酸重复激酶 2 (LRRK2) 是帕金森病 (PD) 最常见的已知病因。 LRRK2 是一种大型细胞质蛋白 (2527 个氨基酸)，包含 GTP 酶和激酶活性。虽然人们一直在努力开发 LRRK2 靶向疗法，但到目前为止，这些疗法都没有被用于临床治疗。临床环境。因此，探索和鉴定大 LRRK2 蛋白中的新治疗位点可能为PD干预提供新途径。最近的研究表明 LRRK2 GTPase 结构域发挥着 LRRK2 功能中发挥重要作用。 GTPase 结构域内的 PD 连锁 LRRK2 突变会改变任一 GTP 结合或 GTP 酶活性。通过基因改变或药理学抑制消除 GTP 结合减弱 LRRK2 激酶活性并防止神经退行性变。值得注意的是，晶体结构 LRRK2 GTPase 结构域显示它是一个二聚体，生物学研究表明 LRRK2 可能需要二聚化作为参与细胞过程和神经元生长的功能蛋白。在这个提案中，我们提议使用计算机辅助药物靶向 LRRK2 GTPase 结构域并识别二聚化抑制剂设计（CADD）和生物筛选。我们将测试通过小分子阻断 LRRK2 二聚化的假设分子可以减轻 LRRK2 细胞和果蝇模型中 LRRK2 诱导的神经变性。这些研究将验证阻断 LRRK2 GTPase 结构域二聚化是否是一个可行的目标开发PD干预的新型治疗药物，并为PD干预提供新的药理学工具 LRRK2 相关的发病机制和治疗研究。