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

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2023 · $44,057

## Abstract

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 Prof...

## Key facts

- **NIH application ID:** 10680372
- **Project number:** 5F31AG076334-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mara Fattah
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $44,057
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680372

## Citation

> US National Institutes of Health, RePORTER application 10680372, Development of Novel Synthetic Proteomimetics for Mediating Tauopathy in Alzheimer's Disease (5F31AG076334-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10680372. Licensed CC0.

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