Chapter 10: α-Helix Mimetics as Inhibitors of Protein–Protein Interactions

A significant number of protein–protein interactions (PPI) have been identified as being α-helix mediated, whereby a helical motif from one protein docks onto the surface of its partner protein making a dominant contribution to the binding free energy of the interaction. The prevalence of the α-helix as the most abundant secondary structural motif offers further evidence that developing molecules to topologically and/or topographically mimic the α-helix might provide a “generic” approach for PPI inhibition. This chapter will describe the development of topological and topographical mimics as inhibitors of α-helix mediated PPIs, focusing on design, synthetic approaches, and characterization of their performance as PPI inhibitors against an array of therapeutically important targets.