Short Peptide Conjugate Functionalized with 18-Crown-6 as a Therapeutic Reagent for Treating Alzheimer’s Disease

Sarkar, Soumyadeep (2025) Short Peptide Conjugate Functionalized with 18-Crown-6 as a Therapeutic Reagent for Treating Alzheimer’s Disease. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Soumyadeep Sarkar (20MS054)) 20MS054_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (2MB)

Abstract

Alzheimer’s disease (AD) is characterized by the pathological accumulation of amyloid-β (Aβ) peptides, particularly the highly aggregation-prone Aβ-42 isoform. Specific hydrophobic segments within Aβ-42, notably the 16LVFF20 motif and the C-terminal domain, play key roles in driving fibrillization and the formation of neurotoxic oligomers and β-sheet-rich fibrils. These aggregates disrupt neuronal homeostasis by triggering synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) leakage, and neuronal cell death. Although numerous anti-amyloid strategies have been proposed, challenges such as insufficient specificity, limited BBB permeability, and suboptimal therapeutic efficacy continue to hinder clinical progress. In this study, we present CFP (Crown ether-functionalized Peptide), a rationally designed, multifunctional peptide-based molecule engineered to selectively inhibit Aβ-42 aggregation and destabilize existing fibrils. CFP integrates three functional components: an LVFF peptide sequence that selectively binds the aggregation-prone 16KLVFF20 region of Aβ-42; a crown ether moiety that forms a stable inclusion complex with Lys16 (Ka ≈ 9.52 × 10⁴ M⁻¹); and a polyethylene glycol (PEG) chain that improves solubility and facilitates BBB penetration. Mechanistic studies show that CFP disrupts inter-peptide interactions essential for β-sheet formation, effectively inhibiting fibrillization and promoting the disassembly of preformed aggregates. In vitro assays, including TEM, Thioflavin T fluorescence, and Circular Dichroism spectroscopy, confirmed CFP’s dual inhibitory and disaggregating activity. These findings highlight the therapeutic potential of CFP as a novel supramolecular agent that addresses critical limitations in current anti-amyloid strategies. By combining high target specificity, efficient BBB permeability, and the ability to both prevent and reverse Aβ aggregation, CFP emerges as a promising candidate for further development in the treatment of Alzheimer’s disease, offering a refined approach to modulating amyloid pathology at the molecular level.

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