d-Amino acid mutation of PMI as potent dual peptide inhibitors of p53-MDM2/MDMX interactions

Xiang Li; Chao Liu; Si Chen; Honggang Hu; Jiacan Su; Yan Zou

doi:10.1016/j.bmcl.2017.09.014

d-Amino acid mutation of PMI as potent dual peptide inhibitors of p53-MDM2/MDMX interactions

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4678-4681. doi: 10.1016/j.bmcl.2017.09.014. Epub 2017 Sep 7.

Authors

Xiang Li¹, Chao Liu², Si Chen², Honggang Hu², Jiacan Su³, Yan Zou⁴

Affiliations

¹ Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China; Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, United States.
² Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
³ Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: drsujiacan@163.com.
⁴ Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: zouyan@smmu.edu.cn.

PMID: 28916339
DOI: 10.1016/j.bmcl.2017.09.014

Abstract

According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs.

Keywords: MDM2/MDMX; P53; PMI; Peptides; Tumor; d-Amino acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amino Acids / metabolism
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival
Circular Dichroism
Humans
Liposomes / chemistry
Molecular Dynamics Simulation
Peptide Library
Peptides / chemistry
Peptides / metabolism*
Peptides / pharmacology
Protein Interaction Domains and Motifs / drug effects
Protein Structure, Tertiary
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 / metabolism*
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / metabolism*

Substances

Amino Acids
Liposomes
Peptide Library
Peptides
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-mdm2