Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Regular Articles
Elaboration of Non-naturally Occurring Helical Tripeptides as p53–MDM2/MDMX Interaction Inhibitors
Aoze SuYuko TabataKiyono AokiAkane SadaRieko OhkiSatoru NagatoishiKouhei TsumotoSiyuan WangYuko OtaniTomohiko Ohwada
Author information

2021 Volume 69 Issue 7 Pages 681-692


Protein–protein interactions (PPIs) are often mediated by helical, strand and/or coil secondary structures at the interface regions. We previously showed that non-naturally occurring, stable helical trimers of bicyclic β-amino acids (Abh) with all-trans amide bonds can block the p53–MDM2/MDMX α-helix–helix interaction, which plays a role in regulating p53 function. Here, we conducted docking and molecular dynamics calculations to guide the structural optimization of our reported compounds, focusing on modifications of the C-terminal/N-terminal residues. We confirmed that the modified peptides directly bind to MDM2 by means of thermal shift assay, isothermal titration calorimetry, and enzyme-linked immunosorbent assay (ELISA) experiments. Biological activity assay in human osteosarcoma cell line SJSA-1, which has wild-type p53 and amplification of the Mdm2 gene, indicated that these peptides are membrane-permeable p53–MDM2/MDMX interaction antagonists that can rescue p53 function in the cells.

Fullsize Image
Information related to the author
© 2021 The Pharmaceutical Society of Japan
Previous article Next article