α‑Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions

The
use of peptidomimetic scaffolds is a promising strategy for
the inhibition of protein–protein interactions (PPIs). Herein,
we demonstrate that sulfono-γ-AApeptides can be rationally designed
to mimic the p53 α-helix and inhibit p53–MDM2 PPIs. The
best inhibitor, with Kd and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is
among the most potent unnatural peptidomimetic inhibitors disrupting
the p53–MDM2/MDMX interaction. Using fluorescence polarization
assays, circular dichroism, nuclear magnetic resonance spectroscopy,
and computational simulations, we demonstrate that sulfono-γ-AApeptides
adopt helical structures resembling p53 and competitively inhibit
the p53–MDM2 interaction by binding to the hydrophobic cleft
of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed
promising cellular activity by enhancing p53 transcriptional activity
and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides
exhibited remarkable resistance to proteolysis, augmenting their biological
potential. Our results suggest that sulfono-γ-AApeptides are
a new class of unnatural helical foldamers that disrupt PPIs.