α-Synuclein Dimers as Potent Inhibitors of Fibrillization

0511507 - ÚOCHB 2020 RIV US eng J - Journal Article
Kyriukha, Yevhenii A. - Afitska, Kseniia - Kurochka, Andrii - Sachan, Shubhra - Galkin, Maksym - Yushchenko, Dmytro A. - Shvadchak, Volodymyr V.
α-Synuclein Dimers as Potent Inhibitors of Fibrillization.
Journal of Medicinal Chemistry. Roč. 62, č. 22 (2019), s. 10342-10351. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR(CZ) GJ18-06255Y
Institutional support: RVO:61388963
Keywords : protecting groups * aggregation * binding
OECD category: Biochemistry and molecular biology
Impact factor: 6.205, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01400

Aggregation of the neuronal protein α-synuclein into amyloid fibrils plays a central role in the development of Parkinson’s disease. Growth of fibrils can be suppressed by blocking fibril ends from their interaction with monomeric proteins. In this work, we constructed inhibitors that bind to the ends of α-synuclein amyloid fibrils with very high affinity. They are based on synthetic α-synuclein dimers and interact with fibrils via two monomeric subunits adopting conformation that efficiently blocks fibril elongation. By tuning the charge of dimers, we further enhanced the binding affinity and prepared a construct that inhibits fibril elongation at nanomolar concentration (IC50 ≈ 20 nM). To the best of our knowledge, it is the most efficient inhibitor of α-synuclein fibrillization.
Permanent Link: http://hdl.handle.net/11104/0301755