Inhibitors of Alzheimer's Disease Amyloidosis

阿尔茨海默病淀粉样变性的抑制剂

• 批准号: 6752122
• 负责人: ALAN D. SNOW
• 金额: $ 9.74万
• 依托单位: PROTEOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752122
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; blood brain barrier; drug design /synthesis /production; drug screening /evaluation; electron microscopy; fluorimetry; inhibitor /antagonist; isoelectric point; laminin; neurofilament; neurotoxicology; peptide chemical synthesis; protein purification; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million American, which is expected to double in incidence in the next 25 years. AD is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (ABeta), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. AB amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and years of disease onset. Our Phase I SBIR studies demonstrated that the basement membrane protein laminin acts as a potent inhibitor of AB fibril formation, both in vitro and in vivo. Following elastase digestion and sequencing, an AB-binding site on laminin was localized to the C-terminal globular domain repeats on the laminin Al chain, within a 55-kDa region. A 12 amino acid peptide was futher identified within the 4th globular domain of laminin Al to be a potent inhibitor of ABeta fibrillogenesis. Following the screening of over 300 overlapping 12-14 amino acid peptides of various laminin alpha-chain globular domains, we identified six ideal peptide candidates (each 12-13 amino acids in length) that were found to be potent inhibitors of ABeta amyloid fibril formation, and which cause a disruption of pre-formed AD amyloid fibrils. Based on these promising results, Phase II SBIR studies will involve the synthesis of related peptide analogs (i.e. D-amino acids, smaller truncated peptides) derived from the six parent form laminin globular domain-derived peptides with the goal of optimizing new peptides that have the ability to 1) inhibit All fibril formation and disrupt/disassemble preformed All fibrils, 2) inhibit All-induced toxicity, 3) resist rapid bio-degradation, 4) cross the blood-brain barrier, and 5) retard or reverse AD-like amyloid plaque pathology in a transgenic mouse model of AD. These studies are anticipated to lead to the identification of a new peptide candidate for the treatment of All amyloidosis in AD and related disorders.

描述（由申请人提供）：阿尔茨海默病（AD）是一种退行性疾病， 临床上表现为记忆力逐渐丧失的脑部疾病， 认知，推理，判断和情绪稳定，逐渐导致 严重的精神恶化最终死亡AD是导致 老年痴呆症，今天影响4-5百万美国人，这是 预计在未来25年内发病率会翻倍。AD的特征在于 不溶性纤维状淀粉样蛋白沉积物的脑积累， β-淀粉样蛋白（ABeta），无论是作为细胞外淀粉样蛋白斑块， 脑实质或血管壁中。AB淀粉样蛋白形成、沉积和 据信，脑中的持久性在AD发病机制中起核心作用， 导致神经元丢失和记忆功能障碍，因此已经成为 是开发治疗AD新药的中心目标， 发病的年份。 我们的I期SBIR研究表明，基底膜蛋白 层粘连蛋白作为AB纤维形成的有效抑制剂，无论是在体外还是在体内， vivo.在弹性蛋白酶消化和测序后，在细胞膜上的AB结合位点被扩增。 层粘连蛋白定位于层粘连蛋白的C-末端球状结构域重复序列 Al链，在55-kDa区域内。进一步鉴定了一个12个氨基酸的多肽 在层粘连蛋白A1的第4球状结构域内，是ABeta的有效抑制剂 纤维形成在筛选了超过300个重叠的12-14个氨基酸后， 我们鉴定了各种层粘连蛋白α链球状结构域的酸性肽， 发现了六种理想的候选肽（每种长度为12-13个氨基酸）， 是ABeta淀粉样蛋白原纤维形成的有效抑制剂， 破坏预先形成的AD淀粉样蛋白原纤维。基于这些有希望的结果， 第二阶段SBIR研究将涉及相关肽类似物的合成 (i.e. D-氨基酸，较小的截短肽）， 形成层粘连蛋白球状结构域衍生肽， 具有以下能力的肽：1）抑制All原纤维形成， 破坏/分解预先形成的All原纤维，2）抑制All诱导的毒性，3） 抵抗快速生物降解，4）穿过血脑屏障，5）延缓 或逆转AD转基因小鼠模型中的AD样淀粉样斑块病理。 这些研究预计将导致一种新的肽的鉴定 用于治疗AD和相关疾病中的所有淀粉样变性的候选物。