Inhibition of ?-catenin/B cell lymphoma 9 protein-protein interaction using ?-helix-mimicking sulfono-?-AApeptide inhibitors.

ABSTRACT: The rational design of ?-helix-mimicking peptidomimetics provides a streamlined approach to discover potent inhibitors for protein-protein interactions (PPIs). However, designing cell-penetrating long peptidomimetic scaffolds equipped with various functional groups necessary for interacting with large protein-binding interfaces remains challenging. This is particularly true for targeting ?-catenin/BCL9 PPIs. Here we designed a series of unprecedented helical sulfono-?-AApeptides that mimic the binding mode of the ?-helical HD2 domain of B Cell Lymphoma 9 (BCL9). Our studies show that sulfono-?-AApeptides can structurally and functionally mimic the ?-helical domain of BCL9 and selectively disrupt ?-catenin/BCL9 PPIs with even higher potency. More intriguingly, these sulfono-?-AApeptides can enter cancer cells, bind with ?-catenin and disrupt ?-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is much more potent than the BCL9 peptide. Furthermore, our enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-?-AApeptides, with no degradation in the presence of pronase for 24 h, augmenting their biological potential. This work represents not only an example of helical sulfono-?-AApeptides that mimic ?-helix and disrupt protein-protein interactions, but also an excellent example of potent, selective, and cell-permeable unnatural foldameric peptidomimetics that disrupt the ?-catenin/BCL9 PPI. The design of helical sulfono-?-AApeptides may lead to a new strategy to modulate a myriad of protein-protein interactions.

SUBMITTER: Sang P 

PROVIDER: S-EPMC6561201 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature