A dimethylbromobenzene-cysteine stapled peptide dual inhibitor of the p53-MDM2/MDMX interactions

Abstract

Aim: Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, thereby playing a critical role in protecting cells from malignant transformation. The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival. Methods: In this work, we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas. Moreover, we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at (i, i+4) positions, and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX, termed p53-MDM2/MDMX inhibitor (PMI). Results: Notably, all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinity as PMI. More importantly, this stapling functionally rescued PMI that, on its own, failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation. Conclusion: Taken together, this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy, but promises an important new tool for peptide drug discovery and development for a variety of human diseases.

A general-purpose Nanohybrid fabricated by Polymeric Au(I)-peptide precursor to wake the function of Peptide Therapeutics

“…In reality, however, peptide therapeutics, particularly those targeting intracellular PPIs, always suffer from two inherent pitfalls: poor proteolytic stability and low cytomembrane permeability 2 , 5 . To alleviate these pharmacological hurdles, a fast-growing number of choreographed modifications for proteolytic resistance and well-designed vehicles for targeted delivery have emerged in ways of clinical peptide translations 2 , 5 - 7 . Notwithstanding some successes in optimizing therapeutic peptides by these two methods, it is still challenging to convert intracellular PPIs into clinical trials, and no drug, as yet, has been approved for clinical application in this target class to our knowledge 8 - 10 .…”

Targeted disruption of the BCL9/β-catenin interaction by endosomal-escapable nanoparticles functionalized with an E-cadherin-derived peptide

“…To confirm this, an ECRV-mimicking peptide consisting of 28 residues (Seq:ESDQDQDYDYLNEWGNRFKKLADMYGG) was synthesized by solid-phase peptide synthesis with Fmoc chemistry [43][44][45][46][47]. Using isothermal titration calorimetry (ITC), we quantified direct interactions of ECRV with the ARD of β-catenin.…”

Assembling BH3-mimic peptide into a nanocluster to target intracellular Bcl2 towards the apoptosis induction of cancer cell

“…The attractive capacity of peptide for stabilizing or disrupting protein-protein interactions is heavily compromised. To overcome the deficiency of proteolytic resistance, a battery of chemically modifying peptides were developed, such as sidechain-stapled peptides [17,18], backbonecyclized (circular) peptides [19,20], D-peptides [16,21,22] and peptide-grafted miniature proteins [23,24]. Besides, in order to solve the problem of the inefficacious cellular internalization, various peptide drug carriers were developed [25][26][27][28][29][30][31][32].…”