α-Synuclein Dimers as Potent Inhibitors of Fibrillization

Kyriukha, Yevhenii A.; Afitska, Kseniia; Kurochka, Andrii; Sachan, Shubhra; Galkin, Maksym; Yushchenko, Dmytro A.; Shvadchak, Volodymyr V.

doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01400

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α-Synuclein Dimers as Potent Inhibitors of Fibrillization

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SYSNO ASEP	0511507
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	α-Synuclein Dimers as Potent Inhibitors of Fibrillization
Author(s)	Kyriukha, Yevhenii A. (UOCHB-X) Afitska, Kseniia (UOCHB-X)_{ORCID, RID} Kurochka, Andrii (UOCHB-X)_ORCID Sachan, Shubhra (UOCHB-X) Galkin, Maksym (UOCHB-X)_ORCID Yushchenko, Dmytro A. (UOCHB-X)_{ORCID, RID} Shvadchak, Volodymyr V. (UOCHB-X)_{ORCID, RID}
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 62, č. 22 (2019), s. 10342-10351
Number of pages	10 s.
Language	eng - English
Country	US - United States
Keywords	protecting groups ; aggregation ; binding
Subject RIV	CE - Biochemistry
OECD category	Biochemistry and molecular biology
R&D Projects	GJ18-06255Y GA ČR - Czech Science Foundation (CSF)
Method of publishing	Limited access
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000500420100021
EID SCOPUS	85074723394
DOI	10.1021/acs.jmedchem.9b01400
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418
Year of Publishing	2020
Electronic address	https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01400

Number of the records: 1