Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics

β-Strands are a fundamental component of protein structure, and these extended peptide regions serve as binding epitopes for numerous protein–protein complexes. However, synthetic mimics that capture the conformation of these epitopes and inhibit selected protein–protein interactions are rare. Here we describe covalent and noncovalent β-hairpin mimics of an extended strand region mediating the Tcf4/β-catenin interaction. Our efforts afford a rationally designed lead for an underexplored region of β-catenin, which has been the subject of numerous ligand discovery campaigns.