Title: Inhibition of A-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends
Abstract: Misfolding of the protein α-synuclein (αSyn) into amyloid fibrils plays a central role in the development of Parkinson's disease, a neurodegenerative disorder that has no cure at present. The majority of existing approaches for inhibition of αSyn fibril formation are based on stabilizing the native disordered 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. We decided to use a different approach and to target fibril ends, reactive species present at much lower concentrations. We designed a chimeric protein consisting of αSyn and a bulky globular protein. αSyn moiety ensures selective binding of the inhibitor to αSyn fibril end while globular protein creates a steric hindrance and prevents binding of αSyn monomers to the end capped by the inhibitor. This approach permits inhibition of fibril formation at inhibitor concentrations much lower than the concentration of monomeric αSyn (IC50 is 850 nM). We studied kinetic mechanism of the inhibition and found that the inhibitor efficiency is limited mostly by its slow binding to the fibril end [1] and it is therefore the most promising direction for the further improvements. Our work demonstrates that blocking of αSyn fibril ends is an effective approach to inhibit fibril growth and provides insights for development of effective inhibitors of αSyn aggregation. [1] V V Shvadchak, K Afitska, D A Yushchenko, Angew Chem Int Ed Engl, 2018, 57, 5690.