QBP1 Mimetics as Therapeutics for Huntington's Disease

QBP1 模拟物作为亨廷顿病的治疗药物

• 批准号: 6788916
• 负责人: JAMES R BURKE
• 金额: $ 18.8万
• 依托单位: PROVID PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788916
• 关键词: Huntington' s disease; binding proteins; biomimetics; biotechnology; cell death; cell line; chemical aggregate; chemical stability; cytotoxicity; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; endopeptidases; glutamine; homopeptide; membrane permeability; neuropharmacology; peptide analog; protein binding; protein sequence; protein structure function; synthetic peptide; tissue /cell culture

DESCRIPTION (provided by applicant): Polyglutamine diseases are a group of inherited neurodegenerative diseases, including Huntington's disease, caused by abnormal expansions of the polyglutamine stretch to greater the 40 repeats in the disease protein. These diseases are characterized by selective neuronal degeneration causing motor control dysfunction and, frequently, psychiatric symptoms or dementia. The polyglutamine repeat diseases are uncommon, but devastating because they are relentlessly progressive and no treatments are available. A glutamine binding peptide, QBP1, which inhibits polyglutamine protein aggregation in vitro, is a therapeutic prototype for the polyglutamine diseases. QBP1 effectively blocks polyglutamine aggregation and death in cultured cell models of disease. QBP1 also blocks polyglutamine toxicity in the eye of Drosophila expressing a polyglutamine protein with a pathologic-length repeat and normalizes lifespan. Unfortunately, delivery of therapeutic peptides to the nervous system is limited by proteolysis and poor transport across cell membranes. The goal of this one year proposal is to develop mimetics that duplicate QBPI's effect on polyglutamine repeat disease pathogenesis, by rationally designing peptide analogs which provide conformational constraint, optimize membrane permeability, protease stability, and bioavailability. The discovery process will be expedited by collaboration between Provid Pharmaceuticals (Piscataway, New Jersey), a biotechnology company devoted to developing peptidomimetic drugs, and laboratories at Duke University. During the first year of collaboration we will define the critical pharmacophore necessary for QBPI's activity in an in vitro aggregation assay, design and synthesize new analogs and test lead compounds in cellular assays. Testing a small number of mimetics for efficacy and toxicity in mouse models of polyglutamine repeat disease will be the subject of a later grant application.

描述（由申请人提供）：多聚谷氨酰胺疾病是一组遗传性神经退行性疾病，包括亨廷顿病，由多聚谷氨酰胺链段异常扩展至疾病蛋白中超过 40 个重复而引起。 这些疾病的特征是选择性神经元变性，导致运动控制功能障碍，并且经常导致精神症状或痴呆。多聚谷氨酰胺重复性疾病并不常见，但却具有毁灭性，因为它们会不断恶化且没有可用的治疗方法。谷氨酰胺结合肽 QBP1 可在体外抑制多聚谷氨酰胺蛋白聚集，是多聚谷氨酰胺疾病的治疗原型。 QBP1 可有效阻止疾病培养细胞模型中的多聚谷氨酰胺聚集和死亡。 QBP1 还可以阻断表达具有病理长度重复的聚谷氨酰胺蛋白的果蝇眼中的聚谷氨酰胺毒性，并使寿命正常化。 不幸的是，治疗性肽向神经系统的递送受到蛋白水解和跨细胞膜运输不良的限制。这项为期一年的提案的目标是通过合理设计提供构象约束、优化膜通透性、蛋白酶稳定性和生物利用度的肽类似物，开发复制 QBPI 对多聚谷氨酰胺重复疾病发病机制的作用的模拟物。 Provid Pharmaceuticals（新泽西州皮斯卡塔韦）是一家致力于开发拟肽药物的生物技术公司，与杜克大学实验室之间的合作将加快这一发现过程。在合作的第一年，我们将在体外聚集测定中定义 QBPI 活性所需的关键药效​​团，设计和合成新的类似物，并在细胞测定中测试先导化合物。 在多聚谷氨酰胺重复疾病小鼠模型中测试少量模拟物的功效和毒性将是后续拨款申请的主题。