Stabilizer-guided inhibition of protein-protein interactions

The discovery of novel protein-protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can inform the design of PPI inhibitors (and vice versa). Here, we combine X-ray crystallographic data from both stabilizer- and inhibitor- co-crystal complexes of the adapter protein 14-3-3 to characterize, down to the atomistic scale, inhibitors of the 14-3-3/Tau PPI – a potential Alzheimer’s drug target. The most potent inhibitor notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while enabling potential future access to new synthetically tractable stabilizers of 14-3-3 and other PPIs.