Development of Novel Synthetic Proteomimetics for Mediating Tauopathy in Alzheimer's Disease

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PROJECT SUMMARY Alzheimer’s Disease (AD) is an incurable, progressive neurodegenerative disease drastically affecting 35 million people worldwide who suffer from dementia and cognitive decline. Recently, microtubule associated protein Tau is believed to be an instrumental inducer in AD, as its misfolding and aggregation disrupts homeostasis and results in widespread neuronal dysfunction. Significant clinical challenges remain in current efforts to cap Tau aggregates from growing or degrading large tangles: a) small molecule approaches have nonspecific binding and resultant side effects, b) antibodies trigger an immune response that necessitates modification for each patient, and c) promising Tau binding peptides have poor cell permeability and are easily degraded. To overcome these challenges, this proposal utilizes a new methodology, the Protein-Like Polymer (PLP) for protecting Tau binding peptides from degradation for their sustained delivery to prevent and cap protofibril formation and degrade larger aggregates from spreading using a proteolysis targeting chimera (PROTAC) PLP approach. This synthetic proteomimetic packages peptides together as high-density brush polymers that are modular, scalable, and rapidly formulated using modern, advanced polymerization strategies to offer multivalency, cell penetration, and specific target binding. PLPs exhibit extended circulation half-life compared to small molecules and linear peptides, maintaining strong bioactivity, cell uptake, and disrupting protein-protein interactions (PPIs). Here, we aim to target Tau in two ways: 1. selectively binding to pre-aggregative Tau to dampen aggregation, and 2. to improve PROTACs enzyme stability and deliverability using a novel proteomimetic bioconjugation strategy. Using Ring Opening Metathesis Polymerization (ROMP), I will develop and optimize a library of Tau binding PLPs and Tau PROTAC PLPS. All PLPs will be rigorously characterized and assessed in in vitro degradation and stability studies, as well as efficacy in relevant Tau expressing cells. I will directly compare the performance of the Tau PLPs in cell viability, cellular uptake, Tau binding, and effect on Tau aggregate formations to the native peptides and their corresponding linear PROTACs. This will be done in collaboration with my co-sponsor, Prof. Richard Morimoto, an expert in proteinopathy molecular biology. My sponsor/co-sponsor and I have devised a training plan at Northwestern to develop my independent resesarch skills as a Chemical Biology PhD candidate. I will conduct this interdisciplinary research at Northwestern, taking advantage of technical training at core facilities to develop skills for both this project (disease cell models, chemical synthesis, advanced imaging) and my future independent research career in neurochemistry. I will simultaneously be improving my oral and written science communication, networking at professional development workshops, and impacting my community. Under Profs. Gianneschi and Morimoto, I will cultivate the skills to be an indispensable nanomedicine researcher. With Kirchstein NRSA Support, I will identify and optimize a chemical biology tool or nanotherapeutic for mediating dysregulated Tau in Alzheimer’s Disease to allay the morbidity of our world’s aging population.