Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.

ABSTRACT: We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous pre-fibrillar oligomers in living cells. Our two αSN FRET biosensors provide complementary insight into αSN oligomerization and conformation in order to improve the success of drug discovery campaigns for the treatment of Parkinson's disease. We measure FRET by fluorescence lifetime, rather than traditional fluorescence intensity, providing a structural readout with greater resolution and precision. This facilitates identification of compounds that cause subtle but significant conformational changes in the ensemble of oligomeric states that are easily missed using intensity-based FRET. We screened a 128

SUBMITTER: Braun AR 

PROVIDER: S-EPMC8238948 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature