HTS framework finds small molecules that block tau binding to the LRP1 receptor
- The team built a quantitative assay set around purified LRP1 ligand-binding domain 4, using fluorescence polarization, split luciferase and TR-FRET.
- Tau, RAP and a peptide ligand competed for overlapping binding sites with nanomolar-range affinities across formats.
- A screen on this platform identified small-molecule inhibitors of the interaction, a starting point against tau uptake and spread.
💡 Points
Protein–protein interactions with a receptor ectodomain are tough targets, so three orthogonal assays is the right way to weed out artifacts. I'd treat the hits cautiously until they show activity in cellular tau-uptake assays and clear LRP1's many other ligands, such as ApoE and RAP, without broad liabilities.
High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction ↗