Turning chiral peptides into a racemic supraparticle to induce the self-degradation of MDM2,Journal of Advanced Research

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Turning chiral peptides into a racemic supraparticle to induce the self-degradation of MDM2
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-06-03 , DOI: 10.1016/j.jare.2022.05.009
Wenguang Yang ₁ , Wenjia Liu ₂ , Xiang Li ₃ , Jin Yan ₂ , Wangxiao He ₄

Affiliation

Introduction

Chirality is immanent in nature, and chiral molecules can achieve their pharmacological action through chiral matching with biomolecules and molecular conformation recognition.

Objectives

Clinical translation of chiral therapeutics, particularly chiral peptide molecules, has been hampered by their unsatisfactory pharmaceutical properties.

Methods

A mild and simple self-assembly strategy was developed here for the construction of peptide-derived chiral supramolecular nanomedicine with suitable pharmaceutical properties. In this proof-of-concept study, we design a D-peptide as MDM2 Self-Degradation catalysts (MSDc) to induce the self-degradation of a carcinogenic E3 Ubiquitin ligase termed MDM2. Exploiting a metal coordination between mercaptan in peptides and trivalent gold ion, chiral MSDc was self-assembled into a racemic supraparticle (MSDNc) that eliminated the consume from the T-lymphocyte/macrophage phagocytose in circulation.

Results

Expectedly, MSDNc down-regulated MDM2 in more action than its L-enantiomer termed ^CtrlMSDNc. More importantly, MSDNc preponderantly suppressed the tumor progression and synergized the tumor immunotherapy in allograft model of melanoma through p53 restoration in comparison to ^CtrlMSDNc.

Conclusion

Collectively, this work not only developed a secure and efficient therapeutic agent targeting MDM2 with the potential of clinical translation, but also provided a feasible and biocompatible strategy for the construction of peptide supraparticle and expanded the application of chiral therapeutic and homo-PROTAC to peptide-derived chiral supramolecular nanomedicine.

中文翻译：

将手性肽转化为外消旋超粒子以诱导 MDM2 的自降解

介绍

手性是自然界固有的，手性分子通过与生物分子的手性匹配和分子构象识别来实现其药理作用。

目标

手性疗法，特别是手性肽分子的临床转化因其不令人满意的药物特性而受到阻碍。

方法

这里开发了一种温和简单的自组装策略，用于构建具有合适药物特性的肽衍生手性超分子纳米药物。在这项概念验证研究中，我们设计了一种 D 肽作为 MDM2 自降解催化剂 (MSDc)，以诱导称为 MDM2 的致癌 E3 泛素连接酶的自降解。利用肽中硫醇与三价金离子之间的金属配位，手性 MSDc 自组装成外消旋超粒子 (MSDNc)，消除循环中 T 淋巴细胞/巨噬细胞吞噬作用的消耗。