Chapter 5: Macrocycles as Inhibitors of Protein–Protein Interactions

Protein–protein interactions (PPI) are often characterized by large interacting surfaces which present few features, as opposed to other targets such as enzymes and receptors which usually possess cryptic sites suitable for modulation by small molecules. As a result, classical small molecules have performed poorly as PPI inhibitors. Macrocycles, on the other hand, uniquely combine a large amount of structural information within a topologically restricted space, which makes them privileged structures for PPI modulation. In this chapter, we first discuss some general principles and specific challenges associated with macrocyclic PPI inhibitors, then cover selected examples among two chemical classes of prevalent macrocyclic PPI inhibitors: non-peptidic (with an emphasis on natural products) and peptidic/semi-peptidic macrocycles. Each category is further sub-divided according to therapeutic areas, with an emphasis on cancer, immunology and infectious diseases, then by target.