# Optimization of a Chemokine Receptor Antagonist Peptide as a Synapse Protecting Treatment for Neurodegeneration in Alzheimer's Disease

> **NIH NIH R43** · CREATIVE BIO-PEPTIDES, INC. · 2021 · $499,860

## Abstract

7. Project Summary AD
In response to PAS-19-319, Creative Bio-Peptides, Inc. proposes a novel therapeutic approach to protect and
restore synapses in Alzheimer’s Disease (AD) by blocking multiple chemokine receptors that promote synapse
loss and inhibit their regeneration. Functional impairment in AD results from loss of neuronal spines and
dendrites, preceding and independent of neuronal death. Cofilin-actin rods (rods) are a 1:1 complex of actin and
cofilin whose formation is linked to a cellular prion protein (PrPC) and NADPH oxidase (NOX)-dependent
signaling pathway and represents an early AD pathology. Rods form in neurites under conditions of energetic
and oxidative stress, such as occur in neuroinflammation, and lead to neurite distal atrophy. Synapse function
declines in neurites in which rods have formed compared neurites without rods from the same neuron and rods
are significantly increased in animal models of AD and in human AD brain. Conversely, cognitive deficits in
mouse models of AD are alleviated by decreasing cofilin rods in neurons. Cofilin plays important roles in dendritic
spine dynamics and receptor trafficking and the sequestering of cofilin into rods is detrimental to synaptic
function. Our preliminary data shows that new oral, stable and rapidly brain penetrant peptide analogs of the
clinical use multi-chemokine receptor antagonist (mCRA) DAPTA (Dala1-peptide T-amide) inhibit the formation
of Aβd/t (1 nM)-induced cofilin-actin rods and are neuroprotective. DAPTA reduced microglial activation in the
dentate gyrus, prevented cortical neuronal loss in NBM-lesioned aged animals and promoted robust sprouting
of axons and synapse regeneration in animals. In multiple phase 2 trials conducted by the NIH on subjects with
HIV-associated neurocognitive disorders (HAND), DAPTA normalized functional brain scans and reversed
cognitive deficits in phase 2 trials by chemokine receptor blocking mechanisms related to preventing cofilin rod
formation and protecting synapses. The synapse and neurite extending effects of chemokine blockade were
recently also shown for maraviroc in brain injuries confirming chemokine receptors as translational targets for
drug development. DAPTA was safe in over 600 persons, some for as long as ten years however was not stable
as a nasal spray formulation. It took us many years to create new stable oral analogs of DAPTA with better brain
entry and long half-life and now propose to optimize a lead oral peptide for synapse protecting and restoring
benefits in AD by determining the EC50 values for four oral peptides to inhibit formation of Aβd/t-induced cofilin
rods compared to approved CRA’s maraviroc and AMD3100 in primary mouse hippocampal neuronal cultures.
We will further optimize the neuroprotective effects of peptides in Aβd/t-treated neurons through quantifiable
morphological and architectural assessments of synapse morphology. Once we have identified the optimized
peptide, we will determine the safety and...

## Key facts

- **NIH application ID:** 10322074
- **Project number:** 1R43AG074715-01
- **Recipient organization:** CREATIVE BIO-PEPTIDES, INC.
- **Principal Investigator:** Michael R Ruff
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,860
- **Award type:** 1
- **Project period:** 2021-09-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322074

## Citation

> US National Institutes of Health, RePORTER application 10322074, Optimization of a Chemokine Receptor Antagonist Peptide as a Synapse Protecting Treatment for Neurodegeneration in Alzheimer's Disease (1R43AG074715-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10322074. Licensed CC0.

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