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?-Helix-Mimicking Sulfono-?-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.

ABSTRACT: The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-?-AApeptides can be rationally designed to mimic the p53 ?-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with Kd and IC50 values of 26 nM and 0.891 ?M 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-?-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-?-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-?-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-?-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.

SUBMITTER: Sang P 

PROVIDER: S-EPMC7025332 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Sang Peng P   Shi Yan Y   Lu Junhao J   Chen Lihong L   Yang Leixiang L   Borcherds Wade W   Abdulkadir Sami S   Li Qi Q   Daughdrill Gary G   Chen Jiandong J   Cai Jianfeng J  

Journal of medicinal chemistry 20200203 3

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 <i>K</i><sub>d</sub> and IC<sub>50</sub> 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 polarizat  ...[more]

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