Hybrid Organic-Inorganic Inhibitors of a PDZ Interaction that Regulates the Endocytic Fate of CFTR

摘要

Protein-protein interactions (PPIs) play key roles in cellular processes and human disease, but the proteins involved often lack compact pockets accessible to traditional ligand-discov-ery methods. As first shown for enzyme inhibitors, multiple weak interactions can be combined to yield polyvalent ligands with enhanced potency and specificity, and this strategy has now been extended to "undruggable" PPI targets. Herein, we extend the ideas of fragment-based PPI inhibition to design hybrid structures utilizing cooperative organic-inorganic binding to a target protein (Figure 1 A). In particular, we engineer a stable rhodium(II) metallopeptide that displaces representative peptide ligands from the PDZ domain of the cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand (CAL). PDZ domains are a family of peptide-binding PPI modules named for the first three members: PSD-95, Dlg, and ZO-1.