α‑Synuclein Dimers as Potent Inhibitors of Fibrillization

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 en...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-11, Vol.62 (22), p.10342-10351
Main Authors: Kyriukha, Yevhenii A, Afitska, Kseniia, Kurochka, Andrii S, Sachan, Shubhra, Galkin, Maksym, Yushchenko, Dmytro A, Shvadchak, Volodymyr V
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01400