α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions
Document Type
Article
Publication Date
2020
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.jmedchem.9b00993
Abstract
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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Medicinal Chemistry, v. 63, issue 3, p. 975-986
Scholar Commons Citation
Sang, Peng; Shi, Yan; Lu, Junhao; Chen, Lihong; Yang, Leixiang; Borcherds, Wade; Abdulkadir, Sami; Li, Qi; Daughdrill, Gary W.; Chen, Jiandong; and Cai, Jianfeng, "α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions" (2020). Molecular Biosciences Faculty Publications. 171.
https://digitalcommons.usf.edu/bcm_facpub/171
