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

0490459 - ÚOCHB 2019 RIV DE eng J - Článek v odborném periodiku
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
Grant CEP: GA ČR(CZ) GJ18-06255Y
Institucionální podpora: RVO:61388963
Klíčová slova: alpha-synuclein * amyloid fibrils * inhibitors * kinetics * neurodegenerative disorders
Obor OECD: Biophysics
Impakt faktor: 12.257, rok: 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.
Trvalý link: http://hdl.handle.net/11104/0284697