LEADS FOR ALZHEIMER'S DISEASE FROM CONOPEPTIDE LIBRARIES

肽库中导致阿尔茨海默病的线索

• 批准号: 6210291
• 负责人: GRZEGORZ BULAJ
• 金额: $ 9.87万
• 依托单位: COGNETIX, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6210291
• 关键词: Alzheimer's disease; amyloid proteins; animal poison; calcium channel blockers; drug design /synthesis /production; ligands; neurotoxins; nicotinic receptors; peptide chemical synthesis; peptide library

DESCRIPTION: (Verbatim from the Applicant's Abstract) We propose to identify high-affinity and subtype selective neuronal nicotinic acetylcholine receptor alpha7 ligands from alpha-conopeptide libraries. Such compounds represent novel therapeutic leads to treat Alzheimer's Disiease (AD). Emerging experimental data suggests the interaction of AD causative agen Amyloid beta-peptide with alpha7 receptors could be responsible for the pathological features of AD. Selective blockage of Abeta/alpha7 complex formation with alpha7 ligands is an attractive therapeutic stragegey. Alpha-conopepide ImI isd the most selecgive alpha7 ligand currently available. However, its affinity for human alpha7 receptors can still be improved. Since alpha-conopeptides targe a wide range of nNChRs, and since suble modivication of nAChR ligand can confer drastic change of affinity and selectivity for these ligans, synthesis and screeing of alph-conopeptide libraries could result in the identification human alpha7 ligands with higher affinity. In Phase I we will construct and screen libraries of alpha-conopeptides. In addtion, we will also use the structure-activity relationship data available for ImI to construct libraries with annatural amino acid building blocks. We expect to identify ImI derivatieves with improved affinity and stability from screen ing thesed libraries. In Phase II, we will carry out functional assays on the leads and proceed to subsequent rational drug design researchers. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：（逐字研究申请人的摘要）我们建议识别 高亲和力和亚型选择性神经元烟碱乙酰胆碱受体 来自α-核肽库的α7配体。这样的化合物代表小说 治疗导致治疗阿尔茨海默氏症的疾病（AD）。新兴实验 数据表明AD致病性Agen淀粉样蛋白β-肽与 α7受体可能是AD的病理特征的原因。 选择性阻塞Abeta/Alpha7复合物与Alpha7配体的形成是一种 有吸引力的治疗曲折。 alpha-conpepide imi ISD是最选择的 alpha7配体目前可用。但是，它对人alpha7的亲和力 受体仍然可以改善。由于α-苯甲酸杆菌剂量很广泛 nnchrs，并且由于NACHR配体的Suble Sudivication可以赋予急剧变化 这些配子的亲和力和选择性，合成和盲肠 Alph众肽库可能导致识别人alpha7 配体具有较高的亲和力。在第一阶段，我们将构建和屏幕库 α-苯肽。另外，我们还将使用结构活动 IMI可用的关系数据可用于使用年度氨基的库 酸性构建块。我们希望通过改进来识别IMI衍生物 屏幕库库的亲和力和稳定性。在第二阶段，我们将 对线索进行功能测定，然后进行随后的理性 药物设计研究人员。 拟议的商业应用程序：不可用