CHAPTER 5: Modulation of Protein–Protein Interactions Using Cyclic Peptides

Protein–protein interactions (PPIs) control and regulate most cellular processes, thus offering opportunities for therapeutic intervention. However, the physicochemical features of protein–protein interfaces (large and relatively flat contact patches) make it a serious challenge to develop molecules that can efficiently target them. Peptide ligands are promising starting points to design new inhibitors; however, their intrinsic flexibility in water often results in negligible structure and poor stability in physiological fluids. To solve these drawbacks, peptide cyclization can produce a variety of protein-like structures that enable the modulation of PPIs that were previously considered undruggable. This chapter highlights successful examples of strategies that are used to induce the folding of peptides into bioactive conformations (helices, strands, turns, etc.), which are often found in PPIs. Fragment-based methods and computational tools have evolved in recent years to embrace the qualities of cyclic peptides, providing chemists with smart tools to develop potent and selective ligands. Finally, in vitro display systems take advantage of directed evolution rules to screen large peptide libraries, thus complementing chemical synthesis methods. All in all, we will explore the myriad of opportunities that cyclic peptides can offer in the modulation of PPIs.