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Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aβ42

Puneeth Kumar, DR and Nalawade, SA and Pahan, S and Singh, M and Senapati, DK and Roy, S and Dey, S and Toraskar, SU and Raghothama, S and Gopi, HN (2023) Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aβ42. In: ACS Chemical Neuroscience, 14 (18). pp. 3398-3408.

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Official URL: https://doi.org/10.1021/acschemneuro.3c00302


The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aβ-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aβ42 into fibrils but also disintegrates the aggregated Aβ42 fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aβ42 at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aβ42. This is in sharp contrast to the β-sheet conformation of Aβ42 upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aβ42 showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer�s disease. © 2023 American Chemical Society

Item Type: Journal Article
Publication: ACS Chemical Neuroscience
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to the American Chemical Society.
Keywords: angiotensin II; peptide, Alzheimer disease; cytoskeleton; human; kinetics, Alzheimer Disease; Angiotensin II; Cytoskeleton; Humans; Kinetics; Peptides
Department/Centre: Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Date Deposited: 28 Feb 2024 06:06
Last Modified: 28 Feb 2024 06:06
URI: https://eprints.iisc.ac.in/id/eprint/83573

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