Inhibition of alpha-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends

0490459 - ÚOCHB 2019 RIV DE eng J - Journal Article
Shvadchak, Volodymyr V. - Afitska, Kseniia - Yushchenko, Dmytro A.
Inhibition of alpha-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends.
Angewandte Chemie - International Edition. Roč. 57, č. 20 (2018), s. 5690-5694. ISSN 1433-7851. E-ISSN 1521-3773
R&D Projects: GA ČR(CZ) GJ18-06255Y
Institutional support: RVO:61388963
Keywords : alpha-synuclein * amyloid fibrils * inhibitors * kinetics * neurodegenerative disorders
OECD category: Biophysics
Impact factor: 12.257, year: 2018

Misfolding of the protein alpha-synuclein (alpha Syn) into amyloid fibrils plays a central role in the development of Parkinson's disease. Most approaches for the inhibition of alpha Syn fibril formation are based on stabilizing the native monomeric form of the protein or destabilizing the fibrillized misfolded form. They require high concentrations of inhibitor and therefore cannot be easily used for therapies. In this work, we designed an inhibitor (Inh-beta) that selectively binds the growing ends of alpha Syn fibrils and creates steric hindrance for the binding of monomeric alpha Syn. This approach permits the inhibition of fibril formation at Inh-beta concentrations (IC50=850nm) much lower than the concentration of monomeric alpha Syn. We studied its kinetic mechanism invitro and identified the reactions that limit inhibition efficiency. It is shown that blocking of alpha Syn fibril ends is an effective approach to inhibiting fibril growth and provides insights for the development of effective inhibitors of alpha Syn aggregation.
Permanent Link: http://hdl.handle.net/11104/0284697