Small Molecule Assisted Protein-Protein Interaction Mapping via Peroxidase Activity (MapPEX)

The field of drug discovery has transformed significantly, embracing new induced-proximity paradigms like Targeted Protein Degradation (TPD). Central to TPD are chemical degraders such as PROTACs and molecular glues which co-opts the cell's natural disposal systems by inducing proximity of target proteins with E3 ubiquitin ligases. TPD holds great promise in addressing previously untreatable diseases, yet challenges in fully characterizing endogenous protein-protein interactions (PPIs) are hindering the advancement in designing innovative small molecules that can effectively modulate these interactions, limiting the impact of new therapeutics. Consequently, there is a growing need for innovative techniques to better map PPIs in cells and elucidate TPD-mediated proximity mechanisms. In this context, medicinal chemists and chemical biologists must move beyond traditional efforts to create innovative chemical tools. This is where MapPEX comes into play as a pioneering initiative. Focused on small Molecule Assisted protein-protein interaction mapping via PEroXidase, MapPEX aims to achieve its objectives through the synthesis and characterization of bifunctional conjugates to covalently modify endogenous protein and facilitate the study of transient PPIs. Currently, the proximity labelling methods often rely on disruptive enzymatic genetic tagging methods. In contrast, MapPEX aims to explore a chemical approach to identify PPIs by using cost-effective and biocompatible small molecules for selectively labelling endogenous proteins, thereby preserving their natural functions. The implications of MapPEX go beyond diverse drug discovery endeavours, providing significant empowerment to the scope of TPD and molecular biology. Through its efforts MapPEX aspires to considerably enhance the study and development of innovative molecular therapeutics by streamlining their rational design and unlocking new targets for intervention.