Elaboration of non-naturally occurring helical tripeptides as p53-MDM2/MDMX interaction inhibitors
| Autor: | Kiyono Aoki, Yuko Otani, Yuko Tabata, Aoze Su, Tomohiko Ohwada, Rieko Ohki, Akane Sada, Kouhei Tsumoto, Satoru Nagatoishi, Siyuan Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Thermal shift assay
MDMX Bicyclic molecule Chemistry Cell Cycle Proteins Proto-Oncogene Proteins c-mdm2 Isothermal titration calorimetry Biological activity General Chemistry General Medicine Tripeptide Protein–protein interaction Molecular Docking Simulation Docking (molecular) Proto-Oncogene Proteins Drug Discovery Carbohydrate Conformation Biophysics Humans Tumor Suppressor Protein p53 Oligopeptides Protein Binding |
| Zdroj: | Chemical and Pharmaceutical Bulletin. |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.c21-00238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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