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 ) , [CuI(μ-L)] ₃ , and [AgI(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 [AgI(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 [AgI(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.