# Gamma-AApeptides as novel biomaterials inhibiting Abeta peptide aggregation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $355,839

## Abstract

Alzheimer's disease (AD) is the most common form and devastating dementia. There are no
effective approaches to specifically target and prevent AD pathogenesis. It is accepted that
aggregated fibrillar forms of Aβ peptides are prominent hallmarks and the major cause of AD due
to their toxicity to neurons. As such, Aβ aggregates are the potential targets for the intervention
of AD, as targeting and removal of Aβ fibrils or plaques is expected to eliminate the toxicity of Aβ
aggregates. Although the KLVFF peptide has been served as the major lead to develop potential
probes to target Aβ aggregation, it only weakly recognizes and inhibits Aβ aggregation.
Meanwhile, it is also susceptible to protease degradation.
 We recently developed a novel one-bead one-compound (OBOC) combinatorial library, from
which we identified a potent peptidomimetic that is 100-fold more effective than KLVFF in
disrupting Aβ aggregation in vitro. This peptide material also removes the cytotoxicity of Aβ
aggregates towards N2a neuro-blastoma cells. Furthermore, this lead compound and its
derivative can even significantly remove Aβ plague deposited in the brain of the AD transgenic
mice ex vivo. As such, our long-term goal is to develop novel biomaterials that can prevent, halt
and cure AD. The objective of this proposal, is to advance our preliminary work by developing
new OBOC libraries with enhanced chemodiversity and novel structural classes, so as to identify
and develop more potent and effective AApeptide biomaterials that can target and inhibit fibrillar
formation of Aβ both in vitro and in vivo. We will first design and synthesize new OBOC gamma-
AApeptide libraries with diverse functional groups and constraints by using a range of novel
chemical approaches. Then we will use established screening assay to identify and optimize
ligands that target and inhibit the aggregation of Aβ peptides. The compounds with activity
equivalent or better than the lead compound identified from the preliminary study will be used to
study their ability to inhibit Aβ aggregation both in vitro and in vivo on AD-transgenic mice.
 The proposed study is significant because there is no effective approaches for AD diagnosis
and prevention. Our research will provide novel biomaterials to unravel AD pathogenies and to
develop potential therapeutic agents for cure of AD. The proposed research is innovative
because we not only provide a general approach for the development of novel class of
biomaterials specially targeting Aβ aggregates, in addition, this combinatorial approach can be
easily extended to identify new materials targeting other amyloid diseases such as Huntington's
disease and diabetes diseases.

## Key facts

- **NIH application ID:** 10188364
- **Project number:** 5R01AG056569-05
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** CHUANHAI CAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,839
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188364

## Citation

> US National Institutes of Health, RePORTER application 10188364, Gamma-AApeptides as novel biomaterials inhibiting Abeta peptide aggregation (5R01AG056569-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10188364. Licensed CC0.

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