Multivalent ligands with tailor-made anion binding motif as stabilizers of protein–protein interactions

Lina Bartsch, Maria Bartel, Alba Gigante, Javier Iglesias-Fernández, Yasser B. Ruiz-Blanco, Christine Beuck, Jeroen Briels, Niklas Toetsch, Peter Bayer, Elsa Sanchez-Garcia, Christian Ottmann (Corresponding author), Carsten Schmuck

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.

Original languageEnglish
Pages (from-to)2921-2926
Number of pages6
JournalChemBioChem
Volume20
Issue number23
Early online date9 Jun 2019
DOIs
Publication statusPublished - 2 Dec 2019

Keywords

  • 14-3-3 proteins
  • C-Raf
  • guanidiniocarbonylpyrrol
  • protein–protein interactions
  • stabilizers
  • Tau
  • protein-protein interactions

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