Identification of small molecule dimethyoxyphenyl piperazine inhibitors of alpha-synuclein fibril growth.

ABSTRACT: Alpha-synuclein (asyn) fibril accumulation is the defining feature of Parkinson disease and is a target for disease-modifying treatments. One therapeutic strategy to reduce fibril accumulation is inhibition of asyn fibril growth. We developed a sensitive fluorescence-based fibril growth assay to screen for small molecule inhibitors. After validating the inhibition assay using a previously identified inhibitor, epigallocatechin-3-gallate, we identified compound 1 as a lead for inhibition of fibril growth. We analysed structure-activity relationships with analogs of 1 to optimize inhibition potency. Our results identified two dimethoxyphenyl piperazine analogs with more potent inhibition of in-vitro assembled fibrils, which were further validated with orthogonal assays including kinetic meas

SUBMITTER: Hwang H 

PROVIDER: S-EPMC12475444 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature