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Elaboration of Non-naturally Occurring Helical Tripeptides as p53–MDM2/MDMX Interaction Inhibitors
Chemical & Pharmaceutical Bulletin  (IF1.645),  Pub Date : 2021-07-01, DOI: 10.1248/cpb.c21-00238
Aoze Su, Yuko Tabata, Kiyono Aoki, Akane Sada, Rieko Ohki, Satoru Nagatoishi, Kouhei Tsumoto, Siyuan Wang, Yuko Otani, Tomohiko Ohwada

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.

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