Elaboration of non-naturally occurring helical tripeptides as p53-MDM2/MDMX interaction inhibitors

Aoze Su; Yuko Tabata; Kiyono Aoki; Akane Sada; Rieko Ohki; Satoru Nagatoishi; Kouhei Tsumoto; Siyuan Wang; Yuko Otani; Tomohiko Ohwada

doi:10.1248/cpb.c21-00238

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Elaboration of non-naturally occurring helical tripeptides as p53-MDM2/MDMX interaction inhibitors

Aoze Su, Yuko Tabata, Kiyono Aoki, Akane Sada, Rieko Ohki , Satoru Nagatoishi, Kouhei Tsumoto, Siyuan Wang, Yuko Otani, Tomohiko Ohwada

著者情報

Aoze Su
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yuko Tabata
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Kiyono Aoki
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Akane Sada
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Rieko Ohki 責任著者
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Satoru Nagatoishi
The Institute of Medical Science, The University of Tokyo
Kouhei Tsumoto
The Institute of Medical Science, The University of Tokyo
School of Engineering, The University of Tokyo
Siyuan Wang
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yuko Otani
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Tomohiko Ohwada
Graduate School of Pharmaceutical Sciences, The University of Tokyo

キーワード: helix mimic, protein-protein interaction, p53-MDM2 interaction, p53-MDMX interaction, docking simulation

ジャーナルフリー早期公開

論文ID: c21-00238

DOI https://doi.org/10.1248/cpb.c21-00238

この記事には本公開記事があります。

The final version of this article is now available: Vol. 69 (2021), No. 7 pp. 681-692

詳細

抄録

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 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.

責任著者(Corresponding author)

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