β-Hairpin Peptidomimetics for Protein-Protein Interaction Inhibition

Protein-protein interactions (PPIs) are crucial in many diseases but are often considered “undruggable,” in particular when involving intracellular proteins. Frequently, their large, shallow surfaces cannot be engaged by classic small molecules. Instead, peptide-based approaches have shown promise, offering antibody-like surface recognition with improved cellular uptake. Notably, structurally highly relevant, β-sheet-derived hairpins have not been much explored as PPI inhibitors. These structures, consisting of antiparallel β-strands connected by short turns, are stabilized by interstrand hydrogen bonds and turn-inducing amino acids. Stabilized and cyclic versions potentially have superior binding and uptake properties. This chapter examines strategies for stabilizing β-hairpins, including β-turnβ-turn design, macrocyclization, and crosslinking, to enhance not only their binding affinity but also cellular uptake and biostability.