Abstract
Abstract
Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the
Spectrum Collection
and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (
NanoLuciferase Binary Technology
). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer’s disease and other tauopathies.