A system for the evolution of protein-protein interaction inducers

Molecules that induce interactions between proteins, often referred to as “molecular glues”, are increasingly recognized as important therapeutic modalities and as entry points for rewiring cellular signaling networks. Here, we report a new PACE-based method to rapidly select and evolve molecules that mediate interactions between otherwise non-interacting proteins: rapid evolution of Protein-Protein Interaction Glues (rePPI-G). Proof-of-concept evolutions demonstrated that rePPI-G reduces the “hook” effect of the engineered molecular glues, due at least in part to tuning the interaction affinities of each individual component of the bifunctional molecule. Altogether, this work validates rePPI-G as a continuous, phage-based evolutionary technology for optimizing molecular glues, providing a strategy for developing molecules that reprogram protein-protein interactions.