Coordination of Anle138b to Silver Results in Selective Reduction of a C-Terminal Truncated α-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 α-synuclein proteostasis(definition). Anle138b = 5-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-1H-pyrazole (HL) is undergoing clinical trials as a promising mitigator of α-synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: H₂L(ClO₄), [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 α-synuclein protein aggregation using human α-synuclein preformed fibrils (PFFs). Using two different anti-α-synuclein antibodies, our data suggest 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.