www.hrjournal.net Original Article Open Access Jiang et al. Hepatoma Res 2019;5:5 DOI: 10.20517/2394-5079.2018.97 Hepatoma Research © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. A dimethylbromobenzene-cysteine stapled peptide dual inhibitor of the p53-MDM2/MDMX interactions Wei Jiang 1,# , Liang Jin 2,# , Min Liu 2 , Peng Hou 1 , Wang-Xiao He 3,4 1 Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China. 2 Department of Infectious Diseases, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China. 3 Center for Translational Medicine, School of Life Science and Biotechnology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China. 4 Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. # The two authors contributed equally. Correspondence to: Dr. Peng Hou, Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China. E-mail: phou@xjtu.edu.cn; Dr. Wang-Xiao He, Center for Translational Medicine, School of Life Science and Biotechnology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. E-mail: whe@ihv.umaryland.edu How to cite this article: Jiang W, Jin L, Liu M, Hou P, He WX. A dimethylbromobenzene-cysteine stapled peptide dual inhibitor of the p53-MDM2/MDMX interactions. Hepatoma Res 2019;5:5. http://dx.doi.org/10.20517/2394-5079.2018.97 Received: 30 Aug 2018 First Decision: 7 Dec 2018 Revised: 28 Dec 2018 Accepted: 28 Dec 2018 Published: 13 Feb 2019 Science Editor: Guang-Wen Cao Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu 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