Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Yang W

PROVIDER: S-EPMC10006529 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Yang Wenguang W Liu Wenjia W Li Xiang X Yan Jin J He Wangxiao W

Journal of advanced research 20220603

<h4>Introduction</h4>Chirality is immanent in nature, and chiral molecules can achieve their pharmacological action through chiral matching with biomolecules and molecular conformation recognition.<h4>Objectives</h4>Clinical translation of chiral therapeutics, particularly chiral peptide molecules, has been hampered by their unsatisfactory pharmaceutical properties.<h4>Methods</h4>A mild and simple self-assembly strategy was developed here for the construction of peptide-derived chiral supramole ...[more]

PMID: 35667548

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Project description:Chiral molecular crystals built up by chiral molecules without inversion centers have attracted much interest owing to their versatile functionalities related to optical, magnetic, and electrical properties. However, there is a difficulty in chiral crystal growth due to the lack of symmetry. Therefore, we made the molecular design to introduce intermolecular hydrogen bonds in chiral crystals. Racemic and enantiopure bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) derivatives possessing hydroxymethyl groups as the source of hydrogen bonds were designed. The novel racemic trans-vic-(hydroxymethyl)(methyl)-BEDT-TTF 1, and racemic and enantiopure trans-vic-bis(hydroxymethyl)-BEDT-TTF 2 were synthesized. Moreover, the preparations, crystal structure analyses, and electrical resistivity measurements of the novel achiral charge transfer salt θ(21)-[(S,S)-2]3[(R,R)-2]3(ClO4)2 and the chiral salt α'-[(R,R)-2]ClO4(H2O) were carried out. In the former θ(21)-[(S,S)-2]3[(R,R)-2]3(ClO4)2, there are two sets of three crystallographically independent donor molecules [(S,S)-2]2[(R,R)-2] in a unit cell, where the two sets are related by an inversion center. The latter α'-[(R,R)-2]ClO4(H2O) is the chiral salt with included solvent H2O, which is not isostructural with the reported chiral salt α'-[(S,S)-2]ClO4 without H2O, but has a similar donor arrangement. According to the molecular design by introduction of hydroxy groups and a ClO4 (-) anion, many intermediate-strength intermolecular hydrogen bonds (2.6-3.0 Å) were observed in these crystals between electron donor molecules, anions, and included H2O solvent, which improve the crystallinity and facilitate the extraction of physical properties. Both salts are semiconductors with relatively low resistivities at room temperature and activation energies of 1.2 ohm cm with E a = 86 meV for θ(21)-[(S,S)-2]3[(R,R)-2]3(ClO4)2 and 0.6 ohm cm with E a = 140 meV for α'-[(R,R)-2]2ClO4(H2O), respectively. The variety of donor arrangements, θ(21) and two kinds of α'-types, and their electrical conductivities of charge transfer complexes based upon the racemic and enantiopure (S,S)-2, and (R,R)-2 donors originates not only from the chirality, but also the introduced intermolecular hydrogen bonds involving the hydroxymethyl groups, perchlorate anion, and the included solvent H2O.

Dataset Information

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

Introduction

Objectives

Methods

Results

Conclusion

Publications

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

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