# Recognition of Abeta monomeric helix

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $580,493

## Abstract

Alzheimer’s disease (AD) is the most devastating dementia causing severe global concern. Although the
mechanism of AD pathogenesis is still under debate, it is widely accepted that aggregated fibrillar forms of Aβ
peptides are prominent hallmarks and the major cause of AD due to their toxicity to neurons. Therefore, 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 neuronal toxicity of Aβ aggregates. However, eradication of total Aβ peptides by
antibodies such as the new drug aducanumab could lead to severe side effects, whereas anti-Aβ aggregation
by β-sheet mimetics could only prevent or delay the process of aggregation process and could not disrupt the
formed/existing Aβ aggregation. Therefore, development of more effective molecular probes that not only prevent
but also disrupt Aβ fibril formation is still in an urgent need.
 In contrast to the use of β-sheet mimetics to block Aβ fibrillar growth, recently we designed a series of helical
peptidomimetics that can tightly bind and stabilize monomeric helical Aβ and thereby shifting the equilibrium of
Aβ conformation into off-pathway structure, leading to both potent prevention and disruption of Aβ aggregation,
as well as significant enhancement of neuro cell growth and dendrite branching without virtually any cytotoxicity.
Furthermore, this lead compound could remove Aβ plague deposited in the brain of the AD transgenic mouse
and completely recover the memory of mice in the behavior test. As such, our long-term goal is to develop
novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, which is the first step to
achieve the long-term goal, is to advance our preliminary work by rationally designing structurally related
analogues of the current lead, so as to identify and develop more potent and effective compounds that can tightly
bind and stabilize Aβ monomer and thus prevent and disrupt Aβ aggregation both in vitro and in vivo. We will
first design helical peptidic foldamer bearing diverse functional groups and closely mimic the binding pattern of
our lead compound. Then we will use our established in vitro assays such as 2D-NMR and kinetic binding assays
to identify and optimize our designed compounds that target and inhibit the aggregation of Aβ peptides. The
compounds with activity equivalent or better than the lead compound will be used to study their ability to inhibit
Aβ aggregation both in vitro and in vivo in AD-transgenic mice.
 The proposed study is significant because there is no effective therapeutic strategy for AD diagnosis and
prevention. Our research will provide molecules with novel mechanism to unravel AD pathogenies and to develop
potential molecular probes and therapeutic agents for cure of AD. The proposed research is innovative because
we not only provide a new strategy for the development of novel class of foldameric prevent and disrupt Aβ
aggreg...

## Key facts

- **NIH application ID:** 10792613
- **Project number:** 5R01AG056569-07
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** CHUANHAI CAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,493
- **Award type:** 5
- **Project period:** 2017-09-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792613

## Citation

> US National Institutes of Health, RePORTER application 10792613, Recognition of Abeta monomeric helix (5R01AG056569-07). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10792613. Licensed CC0.

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