Alpha-Helix Mimetics: Progress Toward Effective Modulation of Protein-Protein Complexes

Protein-protein interactions are one of the most common modes of signaling, but can be one of the most challenging to disrupt. This is primarily due to the relatively shallow and hydrophobic nature of the interacting protein surfaces that may extend over large areas. Even so, progress has been made on this frontier using small molecules that mimic key secondary structural motifs, called proteomimetics. In particular, α-helix mimetics have been successful in disrupting protein-protein interactions. This chapter will discuss the variety of approaches taken to obtain α-helical mimicry in low molecular weight, druglike molecules. Targets such as the BCl-2 family of proteins, HDM2-p53, various calmodulin-binding proteins, and gp41 have a wealth of literature describing α-helix mimetics as protein-protein interaction disruptors having therapeutic value in the areas of cancer, Alzheimer's disease, and AIDS. The approaches taken vary from stabilizing the α-helical structure of short peptides to a diversity of non-peptide, small molecule scaffolds allowing for the correct spatial orientation of substituents for interaction with the protein target. This chapter will compare and contrast the various scaffolds successfully shown to inhibit protein-protein interactions.