The inhibition of intracellular protein‐protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co‐activator protein and oncogene β‑catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high‐affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α‐helical β‑catenin‐binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a β‐catenin inhibitor with single‐digit micromolar activity in a cell‐based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

Structure‐Based Design of Bicyclic Helical Peptides That Target the Oncogene β‐Catenin

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