CHAPTER 9: Macrocyclic α-Helical Peptide Drug Discovery

Macrocyclic α-helical peptides have emerged as a promising new drug class and within the scope of hydrocarbon-stapled peptides such molecules have advanced into the clinic. The overarching concept of designing proteomimetics of an α-helical ‘ligand’ which binds its cognate ‘target’ relative to α-helical interfacing protein-protein interactions has been well-validated and expanded through numerous investigations for a plethora of therapeutic targets oftentimes referred to as “undruggable” with respect to other modalities (e.g., small-molecule or proteins). This chapter highlights the evolution of macrocyclic α-helical peptides in terms of target space, biophysical and computational chemistry, structural diversity and synthesis, drug design and chemical biology. It is noteworthy that hydrocarbon-stapled peptides have successfully risen to the summit of such drug discovery campaigns.