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

被引：57

作者：

Sang, Peng ^{[4
]}

Shi, Yan ^{[4
]}

Lu, Junhao ^{[3
]}

Chen, Lihong ^{[3
]}

Yang, Leixiang ^{[3
]}

Borcherds, Wade ^{[2
]}

Abdulkadir, Sami ^{[4
]}

Li, Qi ^{[1
]}

Daughdrill, Gary ^{[2
]}

Chen, Jiandong ^{[3
]}

Cai, Jianfeng ^{[4
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai 201203, Peoples R China

[2] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA

[3] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 USA

[4] Univ S Florida, Dept Chem, Tampa, FL 33620 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 03期

关键词：

AROMATIC OLIGOAMIDE FOLDAMERS; STRUCTURE-BASED DESIGN; BETA(3)-PEPTIDE INHIBITORS; TRANSMEMBRANE PORES; BETA-PEPTIDES; P53; AFFINITY; MIMETICS; MDMX; PEPTOIDS;

D O I：

10.1021/acs.jmedchem.9b00993

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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

引用

页码：975 / 986

页数：12

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