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

作     者：Wei Jiang Liang Jin Min Liu Peng Hou Wang-Xiao He Wei Jiang;Liang Jin;Min Liu;Peng Hou;Wang-Xiao He

作者机构：Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Department of Infectious Diseasesthe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Center for Translational MedicineSchool of Life Science and Biotechnology and Frontier Institute of Science and TechnologyXi’an Jiaotong UniversityXi’an 710049China Institute of Human Virology and Department of Biochemistry and Molecular BiologyUniversity of Maryland School of MedicineBaltimoreMD 21201USA 

出 版 物：《Hepatoma Research》 (肝癌研究（英文版）)

年 卷 期：2019年第5卷第2期

页      面：1-11页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University(XJTU1AF-CRF-2017-003)to Hou P and He WX 

主　　题：Hepatocellular carcinoma p53 stapled peptide dimethylbromobenzene-cysteine 

摘      要：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 *** 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 *** oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53,conferring tumor development and ***: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 ***,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 *** importantly,this stapling functionally rescued PMI that,on its own,failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic ***: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.