Misfolded protein clearance enhancers for Alzheimers therapy

 描述(申请人提供)：阿尔茨海默病(AD)是一种以淀粉样蛋白和tau蛋白平衡缺陷为特征的蛋白质病。因此，加强对参与AD的错折叠蛋白的清除是防治该病的一种有前途的治疗策略。我们一直在开发“分子镊子”(MTS)，它使用一种独特的机制作为错误折叠蛋白质清除增强剂(MPCE)。MT与淀粉样蛋白结合，并将其异常的自组装重塑为无毒和非淀粉样变的结构，这些结构可以通过自然的细胞清除机制有效地降解。我们目前的先导化合物CLR01已被发现在多种体外和体内系统中有效，包括防止A？自组装和毒性，抑制tau聚集，以及减少淀粉样斑块和神经原纤维缠结。 转基因小鼠的大脑。此外，CLR01被证明具有很高的安全边际。然而，CLR01的药理特性有待优化，其对tau的作用有待进一步研究，其作用机制和治疗潜力的某些问题仍有待解答。在本项目中，我们将采用多管齐下的方法优化CLR01‘S的药代动力学，扩大其对tau影响的表征，研究CLR01’S与脑内淀粉样斑块和神经原纤维缠结的结合，并表征不同剂量和治疗时间的CLR01治疗在AD小鼠模型中清除有毒Aü和tau寡聚体、减少突触毒性和改善学习记忆缺陷的能力。预计这项研究将解决目前尚未回答的问题，并为未来MTS的正式发展提供强有力的支持，以预防和改善AD的疾病治疗。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a proteinopathy characterized by deficient proteostasis of amyloid ß-protein and tau. Therefore, enhancement of clearance of the misfolded proteins involved in AD is a promising therapeutic strategy for preventing and treating the disease. We have been developing "molecular tweezers" (MTs) which act as Misfolded-Proteins Clearance Enhancers (MPCEs) using a unique mechanism. MTs bind to amyloidogenic proteins and remodel their abnormal self-assembly into non-toxic and non-amyloidogenic structures that can be efficiently degraded by the natural cellular clearance mechanisms. Our current lead compound, CLR01, has been found to be effective in multiple in vitro and in vivo systems, including prevention of Aß self-assembly and toxicity, inhibition of tau aggregation, and reduction of both amyloid plaques and neurofibrillary tangles in transgenic mouse brain. In addition, CLR01 was shown to have a high safety margin. However, the pharmacological characteristics of CLR01 need to be optimized, its effect on tau needs to be explored further, and certain questions about its mechanism of action and therapeutic potential are yet to be answered. In this project we will use a multi-prong approach to optimizing CLR01's pharmacokinetics, expand the characterization of its effect on tau, study CLR01's binding to amyloid plaques and neurofibrillary tangles in the brain, and characterize the capability of different doses and treatment durations of CLR01 treatment to remove toxic Aß and tau oligomers, reduce synaptotoxicity, and improve learning and memory deficits in a mouse model of AD. The study is expected to address currently unanswered questions and provide strong support for future formal development of MTs towards prevention and disease-modifying treatment of AD.