UNS: Design of Self-Assembling Peptides and their Conjugates as Amyloid Inhibitors

随着人口老龄化，阿尔茨海默病（AD）和其他与年龄相关的神经退行性疾病将继续影响更多的生命，而目前尚无治疗方法。淀粉样蛋白- β (Abeta)肽的聚集被认为是阿尔茨海默病中神经细胞功能障碍和丧失的原因之一，因此抑制Abeta聚集对阿尔茨海默病新疗法的开发具有相当大的前景。然而，现有的抑制剂还不足以作为有效的治疗手段。该项目旨在开发一类新的肽-纳米颗粒抑制剂，具有更好的生物相容性，酶抗性，以及抗β聚集和毒性的传递特性。本研究的目标是：(i)开发一类新的-薄片形成自组装肽（sap）和sap -纳米颗粒偶联物，作为淀粉样蛋白- β (Abeta)抑制剂，具有改善的抑制能力，酶降解能力和血脑屏障（BBB）的渗透性；（ii）建立实用的设计原则，能够一致地解释SAP衍生物和Abeta肽之间的功能相互作用对淀粉样蛋白聚集、毒性和抑制的序列/结构依赖性。为了实现这些目标，将首先开发全新的计算辅助设计工具，从大量肽库中筛选和鉴定SAPs，然后通过实验确定SAPs在Abeta抑制和Abeta诱导的细胞毒性中的作用。然后，将开发sap -纳米颗粒偶联物，通过相互控制纳米颗粒和偶联肽的界面性质来解决sap的毒性、降解和血脑屏障渗透问题。最后，将开发一个多尺度计算平台，整合实验和计算数据，建立sap的聚集特性、膜透性和细胞毒性之间的序列/结构依赖关系，并最终帮助确定一套具有可调序列和结构特性的sap衍生抑制剂的迭代设计规则。肽抑制剂可能对其他神经退行性疾病有潜在的用途，肽材料也可以代表新的基于蛋白质的自组装纳米/生物材料，用于其他生物医学应用。该项目的跨学科性质提供了一个独特的机会，培训和教育各级学生学习结构生物学，生物信息学和工程设计的概念和工具。从提案中获得的知识将通过本科/研究生课程、高影响力期刊、会议演讲、夏季讲习班/实习和其他外展活动传播。

PI: Zheng, Jie Proposal Number: 1510099With the aging population, Alzheimer's (AD) and other age-related neurodegenerative diseases will continue to impact more lives with no cure available. Aggregation of amyloid-beta (Abeta) peptides is thought to contribute to dysfunction and loss of nerve cells in AD, so inhibition of Abeta aggregation holds considerable promise for the development of new therapies for AD. However, the existing inhibitors are not potent enough to be used as effective treatments. This project aims to develop a new class of peptide-nanoparticle inhibitors of improved biocompatibility, enzymatic resistance, and delivery properties against Abeta aggregation and toxicity. The objectives of this research are to (i) develop a new class of beta-sheet-forming self-assembling peptides (SAPs) and SAP-nanoparticle conjugates as amyloid-beta (Abeta) inhibitors with improved inhibitory ability, enzymatic degradation, and blood-brain barrier (BBB) permeability; and (ii) establish practical design principles that can consistently explain the sequence/structural dependence of functional interactions between SAP derivatives and Abeta peptides on amyloid aggregation, toxicity, and inhibition. To achieve these goals, de novo computation-aided design tools will be first developed to screen and identify SAPs from a large pool of peptide library, followed by experimental determination of the role of SAPs in Abeta inhibition and Abeta-induced cell toxicity. Then, SAP-nanoparticle conjugates will be developed to solve the issues of toxicity, degradation, and BBB permeation of SAPs by mutually controlling interfacial properties of both nanoparticles and conjugated peptides. Finally, a multiscale computational platform will be developed to integrate experimental and computational data to establish the sequence/structure-dependent relationship among aggregation property, membrane permeability, and cell toxicity of SAPs, and finally help to determine a set of rules for iterative design of SAP-derived inhibitors with tunable sequence and structural properties. The peptide inhibitors could be potentially useful for other neurodegenerative diseases, and peptide materials can also represent new protein-based self-assembled nano-/bio-materials for other biomedical applications. The interdisciplinary nature of the project provides a unique opportunity to train and educate all-level students to learn the concepts and tools in structural biology, bioinformatics, and engineering design. The knowledge derived from the proposal will be disseminated through undergraduate/graduate courses, high-impact journals, conference presentations, summer workshops/internships, and other outreach activities.