Turning chiral peptides into a racemic supraparticle to induce the self-degradation of MDM2

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. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

A mild and simple self-assembly strategy was developed for the construction of peptide-derived chiral supramolecular nanomedicine with suitable pharmaceutical properties. The study demonstrated the potential of chiral supramolecular nanomedicine in suppressing tumor progression and enhancing tumor immunotherapy.