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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Authors. Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for in silico mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent in silico docking analysis, and the most promising candidates were tested in vitro and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation in vitro and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.
Author(s): Ali TT, Merghani M, Al-Azzani M, Gatzemeier LM, Hoppert M, Kaloyanova D, Outeiro TF, Neumann P, Popova B, Braus GH
Publication type: Article
Publication status: Published
Journal: European Journal of Medicinal Chemistry
Year: 2025
Volume: 289
Print publication date: 05/05/2025
Online publication date: 26/02/2025
Acceptance date: 24/02/2025
Date deposited: 10/03/2025
ISSN (print): 0223-5234
ISSN (electronic): 1768-3254
Publisher: Elsevier Masson SAS
URL: https://doi.org/10.1016/j.ejmech.2025.117452
DOI: 10.1016/j.ejmech.2025.117452
Data Access Statement: Data will be made available on request.
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