Non-naturally Occurring Helical Molecules Can Interfere with p53–MDM2 and p53–MDMX Protein–Protein Interactions

• Su Aoze

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Wang Siyuan

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Sada Akane

  Laboratory of Fundamental Oncology, National Cancer Center Research Institute

• Otani Yuko

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Zhai Luhan

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Liu Xin

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Sayama Misa

  Graduate School of Pharmaceutical Sciences, University of Tokyo

• Ohki Rieko

  Laboratory of Fundamental Oncology, National Cancer Center Research Institute

• Ohwada Tomohiko

  Graduate School of Pharmaceutical Sciences, University of Tokyo

Abstract

We have discovered that β-amino acid homooligomers with cis- or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike α-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are autogenous conformations that are stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. A structural overlap comparison of helical cis/trans bicyclic β-proline homooligomers with typical α-helix structure of α-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridgehead substituents of the present homooligomers point outwards from the helical surface. We were interested to know whether such non-naturally occurring divergent helical molecules could mimic α-helix structures. In this study, we show that bicyclic β-proline oligomer derivatives inhibit p53–MDM2 and p53–MDMX protein–protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.

Journal

• Chemical and Pharmaceutical Bulletin

  Chemical and Pharmaceutical Bulletin 67 (10), 1139-1143, 2019-10-01

  The Pharmaceutical Society of Japan

Keywords

• helix
• β-proline
• protein–protein interaction
• p53–MDM2 interaction
• p53–MDMX interaction

Details

• CRID: 1390564227317353472
• NII Article ID: 130007722045
• NII Book ID: AA00602100
• DOI: 10.1248/cpb.c19-00501
• ISSN: 13475223
• ISSN: 00092363
• NDL BIB ID: 029983922
• PubMed: 31582633
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I029983922
• Web Site: https://www.jstage.jst.go.jp/article/cpb/67/10/67_c19-00501/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2020205593
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed