QBP1 Mimetics as Therapeutics for Huntington's Disease

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，包括亨廷顿氏病，由多聚谷氨酰胺拉伸异常扩张引起，超过疾病蛋白中的40个重复。这些疾病的特点是选择性神经元变性，引起运动控制功能障碍，并经常出现精神症状或痴呆。聚谷氨酰胺重复疾病并不常见，但却具有毁灭性，因为它们不断发展，而且没有治疗方法。谷氨酰胺结合肽QBP1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阻断聚谷氨酰胺聚集和死亡。QBP1也阻断了果蝇眼中的聚谷氨酰胺毒性，表达具有病理长度重复的聚谷氨酰胺蛋白，并使寿命正常化。

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.