Unknown

Dataset Information

0

?-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

Json Xml
altmetric image

Publications

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]

Similar Datasets

Unknown Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors.
| S-EPMC6561201 | biostudies-literature
Unknown α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged In Vivo Activity.
| S-EPMC8903076 | biostudies-literature
Unknown Aggregation-Induced Emissive and Circularly Polarized Homogeneous Sulfono-γ-AApeptide Foldamers.
| S-EPMC7567131 | biostudies-literature
Unknown An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein-Protein Interactions.
| S-EPMC5014220 | biostudies-literature
Unknown MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination.
| S-EPMC3129153 | biostudies-literature
Unknown The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1.
| S-EPMC7228743 | biostudies-literature
Unknown Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein-Protein Interactions.
| S-EPMC8204676 | biostudies-literature
Unknown Competitive binding between dynamic p53 transactivation subdomains to human MDM2 protein: implications for regulating the p53·MDM2/MDMX interaction.
| S-EPMC3436289 | biostudies-literature
Unknown The p53-MDM2/MDMX axis - A chemotype perspective.
| S-EPMC3898590 | biostudies-literature
Unknown Targeting p53-MDM2-MDMX loop for cancer therapy.
| S-EPMC4472007 | biostudies-literature