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变性疾病，包括亨廷顿病，其由多聚谷氨酰胺延伸的异常扩增至疾病蛋白中大于40个重复引起。 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，并经常出现精神症状或痴呆。多聚谷氨酰胺重复疾病是罕见的，但毁灭性的，因为他们是无情的进步，没有治疗。谷氨酰胺结合肽QBP 1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在培养的疾病细胞模型中有效地阻断多聚谷氨酰胺聚集和死亡。QBP1还阻断表达具有病理长度重复的多聚谷氨酰胺蛋白的果蝇眼中的多聚谷氨酰胺毒性，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质水解和跨细胞膜的不良转运的限制。这个为期一年的提案的目标是通过合理设计肽类似物来开发模拟物，其复制QBPI对多聚谷氨酰胺重复疾病发病机制的作用，所述肽类似物提供构象约束、优化膜渗透性、蛋白酶稳定性和生物利用度。 Provid制药公司（皮斯卡特维，新泽西）是一家致力于开发肽模拟药物的生物技术公司，与杜克大学的实验室合作，将加快发现过程。在合作的第一年，我们将确定QBPI在体外聚集试验中活性所需的关键药效团，设计和合成新的类似物，并在细胞试验中测试先导化合物。 在多聚谷氨酰胺重复疾病的小鼠模型中测试少量模拟物的功效和毒性将是稍后拨款申请的主题。