Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease

We report the discovery of two compounds, TKD 150 and TKD152, that promote the aggregation of a-synudein (aSN) using a realtime quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TILD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PAS6, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of alpha-synudeinopathy-related diseases.

Automated summary

This study reports the discovery of two compounds, TKD 150 and TKD152, that promote the aggregation of aSN. Compared to a previously reported proaggregator, PAS6, these two compounds have a stronger proaggregation effect and can shorten the inherent lag time of the RT-QuIC assay, potentially enabling wider use in the clinical diagnosis of alpha-synucleinopathy-related diseases.