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 MSDNc. More importantly, MSDNc preponderantly suppressed the tumor progression and synergized the tumor immunotherapy in allograft model of melanoma through p53 restoration in comparison to MSDNc.

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.