Design of synthetic agents that disrupt protein-protein interactions

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Low-molecular-weight compounds that disrupt protein-protein interactions (PPIs) have tremendous potential applications as clinical agents and as chemical probes forinvestigating intracellular PPI networks. However, disrupting PPIs is extremely difficult due to the large, flat interfaces of many proteins, which often lack structurally defined cavities to which drug-like molecules could bind in a thermodynamically favorable manner. In this study, we examined the module-assembly strategy for designing PPI inhibitors, in which small module compounds are designed and assembled either by covalent linking with a linker, metal coordination, or chemical ligation on the targeted protein surface, to create a multivalent agent. For example, covalent linking of two modules designed for an active site and a PPI interface led to a potent bivalent agent that disrupt transient protein-protein interactions between protein prenyltransferases and K-Ras protein. These agents demonstrated significant inhibition activity against both farnesylation and geranylgeranylation of K-Ras C-terminal oligopeptide. Furthermore, structural modification by introducing guanidyl groups and peptidomimetics improved the cell permeation of agents, resulting in submicromolar inhibitors for FTase in cells.