Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

Significance The design of cell-penetrating long peptidomimetic scaffolds for interacting with large protein binding interfaces is challenging because they involve various necessary functional groups. Here we report the first series of helical sulfono-γ-AApeptides that disrupt protein–protein interactions. Specifically, we discovered that these helical mimetics can structurally and functionally mimic the B Cell Lymphoma 9 (BCL9) helix and disrupt cancer-related β-catenin/BCL9 protein–protein interaction in cells with excellent potency and specificity. Enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-γ-AApeptides, augmenting their biological potential. This strategy could be adapted to target a myriad of other disease-related protein–protein interactions.