"Coordination of Anle138b to Silver Results in Selective Reduction of a C-terminal truncated Alpha-synuclein Protein and Increased Aggregate Size.".

Parkinson's disease (PD) is a prevalent age-related neurodegenerative syndrome, partially thought to be caused by a decrease in alpha-synuclein proteostasis. Anle138b = 5-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-1H-pyrazole (HL), is undergoing clinical trials as a promising mitigator of alpha-synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: H 2 L(ClO 4 ), [Cu I (μ-L)] 3 , and [Ag I (μ-L)] 3 . To better understand the bioviability of these compounds, we monitored their effects in a cell culture model of alpha-synuclein protein aggregation using human alpha-synuclein pre-formed fibrils (PFFs). Using two different anti-alpha-synuclein antibodies, our data suggests that [Ag I (μ-L)] 3 decreases a C-terminal truncated protein that is approximately 12.4 kDa, as well as increases the size and alters the shape of PFF-induced aggregates. This indicates that [Ag I (μ-L)] 3 impacts aggregation in a manner different from HL and may serve as a novel tool for studying C-terminal truncation related aggregation chemistry.