Discovering Calpain Inhibitors for Neurological Diseases

发现神经系统疾病的钙蛋白酶抑制剂

基本信息

批准号：
7365057
负责人：
Jonathan David Glass
金额：
$ 2.5万
依托单位：
EMORY 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：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365057
关键词：
Acute Axon Biological Assay Calcium Calpain Calpain II Chemicals Chemistry Chronic Classification Collaborations Craniocerebral Trauma Cysteine Protease Cytoskeleton Data Development Drug Design Elevation Endopeptidases Enzymes Head Impaired cognition Modeling Molecular Bank Motor Multiple Sclerosis Nerve Degeneration Neuraxis Neurologic Neurologic Dysfunctions Neurons Numbers Numbness Pain Pathogenesis Pathologic Processes Pathway interactions Patients Peptide Hydrolases Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Chemistry Pharmacologic Substance Process Protein Isoforms Protocols documentation Purpose Research Resources Screening procedure Sensory Signs and Symptoms Spinal Cord Spinal cord injury Stroke Structure Therapeutic Agents United States National Institutes of Health Universities calpain inhibitor disability follow-up high throughput screening inhibitor/antagonist nervous system disorder novel novel therapeutics prevent repository small molecule small molecule libraries success tool

项目摘要

DESCRIPTION (provided by applicant): Calpain inhibitors have enormous potential as therapeutic agents for neurological diseases. Calpains are calcium-activated cysteine proteases that are major contributors to the process of axonal and neuronal degeneration. Degeneration of axons leads to the disconnection of neurons from their motor or sensory targets, leading to weakness, numbness, pain, and cognitive impairment. Axonal degeneration underlies neurological dysfunction in stroke, head and spinal cord injury, peripheral neuropathies, and multiple sclerosis. We have had success in preventing axonal degeneration and neurological dysfunction in a model of peripheral neuropathy. We propose to use the Molecular Libraries Screening Center at Emory University for high throughput screening of a large library of small molecules (up to 100,000) for calpain inhibitor activity. We have developed a secondary assay for independent analysis of "hits", and plan for follow-up developmental chemistry for optimizine drug design. Thus, the resources of the MLSCN will allow us to identify new calpain inhibitor compounds that may provide important new treatment for patients with a variety of neurological diseases. The degeneration of axons is a pathological feature common to many neurological diseases that causes neurological disability due to disconnection of neurons from their targets. Preventing axonal degeneration is thus protective, and we are proposing to discover small molecules that can be used for this purpose. The target of our small molecule screen is the calcium-activated protease calpain. Inhibitors of calpain will be developed as novel treatments of neurological diseases.

描述（由申请人提供）：钙蛋白酶抑制剂作为神经系统疾病的治疗剂具有巨大的潜力。 CALPAIN是钙激活的半胱氨酸蛋白酶，是轴突和神经元变性过程的主要因素。轴突的变性导致神经元与其运动或感觉靶标的断开，导致无力，麻木，疼痛和认知障碍。轴突变性是中风，脊髓损伤，周围神经病和多发性硬化症中神经功能障碍的基础。在外周神经病模型中，我们在预防轴突变性和神经功能障碍方面取得了成功。我们建议使用埃默里大学的分子库筛选中心进行高吞吐量筛选，以筛选大型小分子（最高100,000），以进行钙蛋白酶抑制剂活性。我们已经开发了一种用于独立分析“命中”的次要测定，并计划进行优化药物设计的后续发育化学。因此，MLSCN的资源将使我们能够鉴定出可能为患有多种神经系统疾病的患者提供重要新治疗方法的新型钙蛋白酶抑制剂化合物。轴突的变性是许多神经系统疾病常见的病理特征，由于神经元与靶标的断开连接而导致神经系统疾病。因此，防止轴突变性具有保护性，我们建议发现可用于此目的的小分子。我们小分子筛选的目标是钙激活的蛋白酶钙蛋白酶。钙蛋白酶的抑制剂将被开发为神经疾病的新型治疗方法。