AUTHOR=Staats Roxine , Brotzakis Z. Faidon , Chia Sean , Horne Robert I. , Vendruscolo Michele 

TITLE=Optimization of a small molecule inhibitor of secondary nucleation in α-synuclein aggregation

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1155753

DOI=10.3389/fmolb.2023.1155753

ISSN=2296-889X

ABSTRACT=<p>Parkinson’s disease is characterised by the deposition in the brain of amyloid aggregates of α-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of α-synuclein deposits. We report a procedure to enhance the potency of a small molecule to inhibit the aggregate proliferation process using a combination of <italic>in silico</italic> and <italic>in vitro</italic> methods. The optimized small molecule shows potency already at a compound:protein stoichiometry of 1:20. These results illustrate a strategy to accelerate the optimisation of small molecules against α-synuclein aggregation by targeting secondary nucleation.</p>