PPI-Glue · Stabilization of Protein Protein Interactions; transforming molecular glue discovery from art into science

Intrinsically Disordered Proteins (IDPs) represent one of drug discovery’s major challenges. Due to their high degree of conformational freedom, IDPs have no defined pockets for binding small molecules. Molecular glues that can strengthen protein-protein interactions (PPIs) are a revolutionary technology for drug discovery. The hub protein 14-3-3 regulates many IDPs via phosphorylation-dependent PPIs. Stabilization of 14-3-3 PPIs with small molecular glues provides a unique entry point to render IDPs druggable and mitigate the aberrant behaviour of malfunctioning IDPs, for example in neurodegenerative diseases.While inhibition of PPIs by small molecules has expanded the proteome suitable for therapeutic intervention, the opposite chemical-biology strategy of PPI stabilization by small molecular glues is, despite a recent surge of interest, remarkably underexplored. The lack of mechanistically understanding PPI stabilization impedes systematically identifying molecular glues and limits progress to drug IDPs. Based on compelling preliminary data, I propose here that mechanistic understanding of 14-3-3 PPI stabilization will play a crucial role in the discovery of molecular glues for IDPs and transform molecular glue drug discovery from art into science.We will tackle this central question by pursuing two key objectives: Objective 1 – Mechanistically understand PPI stabilization between the 14-3-3 scaffold protein and IDPs. This will address the underlying thermodynamic and kinetic processes, conformational selection, multivalency, cooperativity and selectivity; Objective 2 –Drugging the undruggable -biomolecular condensates and IDPs- via PPI stabilization approaches. The potential for PPI stabilization in the dense environments of biomolecular condensates will be uncovered and a mechanism-driven campaign to identify molecular glues for the 14-3-3/Tau PPI will lead the way to novel drug discovery for neurodegenerative diseases.