Module assembly for designing multivalent mid-sized inhibitors of protein-protein interactions.

Developing clinically relevant synthetic agents that are capable of disrupting protein-protein interactions (PPIs) is now a major goal of scientific research. In an effort to explore new methodologies that are applicable to the design of synthetic PPI inhibitors, we examined a strategy based on the assembly of small module compounds to create multivalent mid-sized agents. This personal account describes three particular approaches based on module assembly: metal-chelating-based ligand assembly, covalent chemical ligation templated by a targeted protein, and bivalent inhibitor design for simultaneous targeting of the active pocket and protein surface. These strategies were shown to be useful for synthesizing minimally sized synthetic agents for targeting PPIs and may enable development of agents that are applicable to inhibition of intracellular PPIs.