Peptidomimetics Inspired by α-Synuclein or Its Chaperone αB-Crystallin Differentially Modulate α-Synuclein Aggregation
Abstract
Aggregation of the α-Synuclein protein in neurons is responsible for synucleinopathies such as Parkinson's Disease. In healthy cells, αSyn is primarly present as monomers. Under pathological conditions, oligomers and fibrils are formed, leading to neuronal toxicity and death. No treatment prevents fatal synucleinopathies. We designed small peptidomimetics based on the structure of αSyn aggregates and on its chaperone protein αB-crystallin. Interestingly, a relationship between the impact of peptidomimetics on the αSyn aggregation process, their sequences and secondary conformation has been evidenced. In vitro and in cellular assays demonstrated that one compound based on αB-crystallin was able to interfere with αSyn folding and aggregation by reducing the formation of oligomers and promoting an off-pathway aggregation. The demonstration that physiological chaperone proteins can be mimicked by small peptide derivatives paves the way for new strategies to design inhibitors of amyloid protein aggregation, a hallmark of around 50 neurodegenerative and systemic amyloid diseases.
Related
- A protease-resistant D-amino acid αA-crystallin mini-chaperone with enhanced chaperone and antioxidant activities protects against amyloid-β proteotoxicity
- Aβ42-Driven α-synuclein Fibril Polymorphism and Distinct Intracellular Aggregation
- Examining the Atypical Structure Adopted by the 37-51 Segment of α-synuclein in the Early Stage of Aggregation
- State-selective inhibition of alpha-synuclein aggregation by de novo oligomer-binding proteins
- Oxidized EGCG redirects α-synuclein aggregation through shear-selected interactions
BibTeX
@article{bisi2026peptidomimetics,
title = {{Peptidomimetics Inspired by α-Synuclein or Its Chaperone αB-Crystallin Differentially Modulate α-Synuclein Aggregation}},
author = {Nicolo Bisi and Josine Kothuis and Julia Kaffy and Helena Pérez Peña and Celina Schulz and Chiara Maria Giulia de Luca and Arianna Ciullini and Ilaria Linda Dellarole and Léa Radal and Fabio Moda and Graziella Cappelletti and Dragos Horvath and Stefano Pieraccini and Wolfgang Hoyer and Frédéric Halgand and Nicolo Tonali and Sandrine Ongeri},
journal = {Journal of Medicinal Chemistry},
year = {2026},
month = oct,
doi = {10.1021/acs.jmedchem.5c02716},
url = {https://hal.science/hal-05778777v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Peptidomimetics Inspired by α-Synuclein or Its Chaperone αB-Crystallin Differentially Modulate α-Synuclein Aggregation
AU - Nicolo Bisi
AU - Josine Kothuis
AU - Julia Kaffy
AU - Helena Pérez Peña
AU - Celina Schulz
AU - Chiara Maria Giulia de Luca
AU - Arianna Ciullini
AU - Ilaria Linda Dellarole
AU - Léa Radal
AU - Fabio Moda
AU - Graziella Cappelletti
AU - Dragos Horvath
AU - Stefano Pieraccini
AU - Wolfgang Hoyer
AU - Frédéric Halgand
AU - Nicolo Tonali
AU - Sandrine Ongeri
PY - 2026
DA - 2026/10/05
JO - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.5c02716
UR - https://hal.science/hal-05778777v1
AB - Aggregation of the α-Synuclein protein in neurons is responsible for synucleinopathies such as Parkinson's Disease. In healthy cells, αSyn is primarly present as monomers. Under pathological conditions, oligomers and fibrils are formed, leading to neuronal toxicity and death. No treatment prevents fatal synucleinopathies. We designed small peptidomimetics based on the structure of αSyn aggregates and on its chaperone protein αB-crystallin. Interestingly, a relationship between the impact of peptidomimetics on the αSyn aggregation process, their sequences and secondary conformation has been evidenced. In vitro and in cellular assays demonstrated that one compound based on αB-crystallin was able to interfere with αSyn folding and aggregation by reducing the formation of oligomers and promoting an off-pathway aggregation. The demonstration that physiological chaperone proteins can be mimicked by small peptide derivatives paves the way for new strategies to design inhibitors of amyloid protein aggregation, a hallmark of around 50 neurodegenerative and systemic amyloid diseases.
SN - 0022-2623
SN - 1520-4804
ER -