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

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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.