Identification of Small Molecule Ligands with NGF Potentiating Activity

具有 NGF 增强活性的小分子配体的鉴定

基本信息

批准号：
7903839
负责人：
Gordon C Ibeanu
金额：
$ 22.03万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903839
关键词：
Affinity Alzheimer&apos s Disease Area Biological Assay Biological Factors Blood - brain barrier anatomy Cell Line Cell Lineage Cell model Cells Chemicals Chemistry Chemosensitization Collection Complex Cues Data Data Quality Defect Dementia Development Enhancers Enzyme-Linked Immunosorbent Assay Fostering Foundations Funding Future Gene Expression Regulation Goals Human Huntington Disease In Vitro Laboratory Research Lateral Lead Ligands Measures Messenger RNA Methods Molecular NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Nerve Growth Factors Neurites Neurodegenerative Disorders Neuronal Differentiation Neurons Neurosciences Outcome Pathway interactions Patients Peptides Pharmacologic Substance Plants Process Property Proteins Publications Regulation Research Research Personnel Role Signal Pathway Small Molecule Chemical Library Specificity Structure Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Translating United States National Institutes of Health Work age related cellular targeting computational chemistry high throughput screening in vivo nervous system disorder neurite growth neurodevelopment neuron loss neurotrophic factor neurotropic novel prevent programs research study scaffold small molecule small molecule libraries tool transmission process

项目摘要

The specific aims of the research described in this application is to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action n promoting neuronal differentiation and survival with regards to new pathways and cellular targets. The objectives in the long-term are to develop invaluable tools to better understand the general mechanisms of activity potentiation and the roles of NGF in fostering the development of neural processes. Identified leads with acceptable therapeutic profiles will progress through SAR with the ultimate goal to develop therapeutic agents that prevent or delay the onset of neurodegeneration caused by defects in molecular and chemical cues that initiate and sustain neurite extension. This research will utilize the approaches of chemoinformatics and HTS to identify novel structures and molecules with core chemical scaffolds that are similar to known potentiators of NGF-dependent neurite extension of natural products origin from a chemical library of small molecules. Active compounds will be characterized for potency, efficacy, selectivity, and specificity in neuronal cell lineages to identify lead compounds. Studies on the mechanism of actions of leads compounds will be initiated to establish novel pathways and cellular targets that interact with identified leads. Successful development of NGF potentiators with therapeutic values will have a tremendous impact in modifying the outcome of age-related neurodegenerative diseases and other dementias.

本申请中描述的研究的具体目标是开发新型有效且选择性小的神经元中 NGF 依赖性活性的分子增强剂，并表征其作用机制 n 促进神经元分化和新通路和细胞靶标的存活。这长期目标是开发宝贵的工具来更好地理解一般机制活性增强以及 NGF 在促进神经过程发育中的作用。已识别线索具有可接受的治疗方案将通过 SAR 取得进展，最终目标是开发治疗方法预防或延缓由分子和化学缺陷引起的神经变性发作的药物启动和维持神经突延伸的线索。本研究将利用以下方法化学信息学和 HTS 来识别具有核心化学支架的新颖结构和分子类似于源自化学物质的天然产物的 NGF 依赖性神经突延伸的已知增强剂小分子库。活性化合物将表征效力、功效、选择性和神经元细胞谱系的特异性来识别先导化合物。作用机制研究先导化合物将被启动，以建立与已识别的相互作用的新途径和细胞靶点领先。具有治疗价值的NGF增强剂的成功研发将产生巨大影响改变与年龄相关的神经退行性疾病和其他痴呆症的结果。