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

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

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

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.

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.

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.