Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells

0543021 - ÚOCHB 2022 RIV US eng J - Článek v odborném periodiku
Priss, Anastasiia - Afitska, Kseniia - Galkin, Maksym - Yushchenko, Dmytro A. - Shvadchak, Volodymyr V.
Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells.
Journal of Medicinal Chemistry. Roč. 64, č. 10 (2021), s. 6827-6837. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR(CZ) GJ18-06255Y
Institucionální podpora: RVO:61388963
Klíčová slova: parkinsons disease * aggregation * brain
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 8.039, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1021/acs.jmedchem.1c00086

Misfolding of the neuronal protein α-synuclein (αSyn) into amyloid fibrils is involved in the development of Parkinson’s disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric αSyn. They were developed based on the recent structural data of the αSyn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded αSyn, nontoxic, and active in cytosol in small concentrations. The best-performing inhibitor shows IC50 ∼10 nM in a cell-based assay, which corresponds to the ∼1:60 molar ratio to αSyn. It can suppress the formation of αSyn aggregates in cells that can be potentially used to slow down the spreading of the pathological aggregates from cell to cell during the course of the PD.
Trvalý link: http://hdl.handle.net/11104/0320331