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：
7288985
负责人：
Gordon C Ibeanu
金额：
$ 10.33万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7288985
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 Class 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 Informatics 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 Range Regulation Research Research Personnel Role Score 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

Affinity Alzheimer&apos s Disease Area Biological Assay Biological Factors Blood - brain barrier anatomy Cell Line Cell Lineage Cell model Cells Chemicals Chemistry Chemosensitization Class 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 Informatics 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 Range Regulation Research Research Personnel Role Score 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

展开

项目摘要

DESCRIPTION (provided by applicant): The specific aims of the research described in this application are to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action in promoting neuronal differentiation and survival with regard 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 chemo-informatics 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 action of lead 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.

描述（由申请人提供）：本申请中描述的研究的具体目的是开发NGF依赖性活性的新型和选择性的小分子增强剂，并表征其在促进新途径和细胞靶标方面促进神经元分化和存活方面的作用机制。从长远来看，目标是开发宝贵的工具，以更好地了解活动增强的一般机制以及NGF在促进神经过程发展中的作用。确定的具有可接受的治疗特征的铅将通过SAR进行，其最终目标是开发治疗剂，以防止或延迟由启动和维持神经扩展的分子和化学线索缺陷引起的神经变性的发作。这项研究将利用化学信息学和HTS的方法来鉴定具有核心化学支架的新型结构和分子，这些结构与NGF依赖性神经产物的已知增强剂相似，自然产物的神经产物延伸来自小分子的化学文库。活性化合物将以神经元细胞谱系中的效力，功效，选择性和特异性为特征，以鉴定铅化合物。将启动有关铅化合物作用机理的研究，以建立与已识别铅相互作用的新型途径和细胞靶标。成功开发具有治疗价值的NGF增强剂将对改变与年龄相关的神经退行性疾病和其他痴呆症的结果产生巨大影响。