Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering

Madita Wolter, Dario Valenti, Peter J Cossar, Laura M Levy, Stanimira Hristeva, Thorsten Genski, Torsten Hoffmann, Luc Brunsveld, Dimitrios Tzalis (Corresponding author), Christian Ottmann (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review


Small-molecule stabilization of protein-protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a "bottom-up" approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine-forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature enables efficient analysis of structure-activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65-subunit-derived peptide of NF-κB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues.

Original languageEnglish
JournalAngewandte Chemie - International Edition
Publication statusE-pub ahead of print - 20 Aug 2020


  • 14-3-3 proteins
  • cooperative effects
  • fragment-based drug discovery
  • imine chemistry
  • protein–protein interactions

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