Rationally designed semisynthetic natural product analogues for stabilization of 14-3-3 protein–protein interactions

Sebastian A. Andrei, Pim de Vink, Eline Sijbesma, Ling Han, Luc Brunsveld, Nobuo Kato, Christian Ottmann, Yusuke Higuchi

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)
4 Downloads (Pure)

Abstract

The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein–protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.

Original languageEnglish
Pages (from-to)13470-13474
Number of pages5
JournalAngewandte Chemie - International Edition
Volume57
Issue number41
DOIs
Publication statusPublished - 8 Oct 2018

Keywords

  • anticancer
  • drug discovery
  • molecular dynamics
  • natural products
  • proteins
  • Humans
  • Crystallography, X-Ray
  • Molecular Dynamics Simulation
  • Diterpenes/chemistry
  • Hydrogen Bonding
  • Drug Design
  • Cell Line, Tumor
  • Protein Binding
  • 14-3-3 Proteins/chemistry
  • Molecular Structure
  • Fluorescence Polarization
  • Biological Products/chemistry

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