# Inhibition of Amyloid Formation by Heterogeneous Nanoparticles with Chaperone-like Activity

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2020 · $178,987

## Abstract

SUMMARY
The formation of amyloid fibrils due to protein aggregation represents a central step in the pathogenesis of many
age-related diseases for which there are no current cures. At the core of this step is the misfolding of one or
more key proteins, which is converted from a natively folded or unfolded state to an aggregation-prone state that
is rich in b-sheet structure. While there have been intensive efforts to develop therapeutic approaches to inhibit
amyloid fiber formation during its initial stages, such strategies have met with only limited success. As such,
there remains a need for alternative strategies to mediate even earlier states of amyloid oligomerization by re-
folding and thus rescuing misfolded proteins prior to aggregating. The overall aim of this proposal is to develop
nanomaterials with chaperone-like activity to promote re-folding of misfolded proteins and thus have therapeutic
potential to inhibit amyloid formation. Specifically, in this approach, we propose to rationally modify nanoparticles
with novel coatings that stabilize the native structure of amyloid-associated proteins and can be delivered in vivo.
Of particular interest will be investigating the extent to which chemically heterogeneous polymer brushes and
mixed lipid bilayers promote re-folding of the protein amyloid-b (Ab42), which is a precursor to amyloid fibers
that are formed in Alzheimer’s disease. In support of this approach, we have previously shown that random co-
polymer brushes composed of poly(ethylene glycol) and poly(sulfobetaine) as well as mixed supported lipid
bilayers compared of varying ratios of 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-
phospho-(1'-rac-glycerol) both stabilized and promoted the re-folding of model proteins, including fibronectin and
nitroreductase. Using coatings made of such materials, we will test the central hypothesis that nanoparticles
coated with dynamic and heterogeneous layers can reduce the conversion of Ab42 to its aggregation-prone state
and prevent amyloid formation via a chaperone-like mechanism. In line with this hypothesis, the specific aims of
this proposal are to: (1) elucidate the mechanism and optimize the composition of heterogeneous coatings for
Ab42 stabilization by nanoparticles via a chaperone-like mechanism (Aim 1) and (2) correlate Ab42 stabilization
by chemically heterogeneous nanoparticles with the inhibition amyloid formation (Aim 2). The chaperone-like
activity of the nanoparticle coatings will be characterized quantitatively using single-molecule biophysical
methods that are uniquely sensitive to monitoring protein structure and dynamics (e.g., re-folding) on surfaces.
To correlate the stabilization of Ab42 with the inhibition of amyloid formation, the impact of the coatings on the
formation of amyloid fibrils will be measured in the presence of coated and uncoated nanoparticles while varying
coating composition. Additionally, the utility of the coated nanoparticles...

## Key facts

- **NIH application ID:** 9901460
- **Project number:** 5R21AG062979-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Joel Kaar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $178,987
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901460

## Citation

> US National Institutes of Health, RePORTER application 9901460, Inhibition of Amyloid Formation by Heterogeneous Nanoparticles with Chaperone-like Activity (5R21AG062979-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901460. Licensed CC0.

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