DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity
Year: 2026
Type: article
Abstract: Alzheimer's disease (AD) pathology is primarily driven by the self-assembly of amyloid-β (Aβ) peptides, a process significantly stabilized through π-π stacking interactions between the aromatic residues Phe19 and Phe20. To competitively disrupt this crucial interaction, we designed novel peptide inhibitors derived from the Aβ recognition motif KLVFFA (Aβ16−21), in which phenylalanine residues were replaced with L-3,4-dihydroxyphenylalanine (DOPA), a residue featuring an enhanced π-stacking and hydrogen-bonding catechol moiety. The DOPA-substituted peptides effectively inhibited Aβ1−42 (Aβ42) aggregation, as demonstrated by Thioflavin T fluorescence assays, circular dichroism spectroscopy, and transmission electron microscopy. These complementary analyses collectively exhibited substantial suppression of β-sheet formation and fibril elongation. Notably, the anti-aggregation potency was dependent on the substitution position, with the Phe19-substituted analogue (KDF) exhibiting superior activity. Molecular simulations further supported this finding, revealing a more favorable binding free energy for KDF compared to the parent peptide. Furthermore, the DOPA-peptides potently mitigated Aβ42-induced neurotoxicity in SH−SY5Y cells, with the dual-substituted analogue providing the highest level of cytoprotection. Collectively, these findings validate that targeted modulation of aromatic interactions through DOPA substitution represents a powerful molecular strategy for controlling Aβ42 self-assembly, presenting these peptides as promising therapeutic leads for AD.
DOI: 10.3390/ijms27219503
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7163130997