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

40 Citations (Scopus)

Abstract

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
Pages (from-to)21520-21524
Number of pages5
JournalAngewandte Chemie - International Edition
Volume59
Issue number48
Early online date20 Aug 2020
DOIs
Publication statusPublished - 23 Nov 2020

Funding

The research was supported by funding from the European Union through the TASPPI project (H2020‐MSCA‐ITN‐2015, grant number 675179), through the Eurotech Postdoctoral Fellow program (Marie Skłodowska‐Curie Co‐funded, grant number 754462) and through The Netherlands Organization for Scientific Research (NWO) via VICI grant 016.150.366 and via Gravity Program 024.001.035. The research was supported by funding from the European Union through the TASPPI project (H2020-MSCA-ITN-2015, grant number 675179), through the Eurotech Postdoctoral Fellow program (Marie Skłodowska-Curie Co-funded, grant number 754462) and through The Netherlands Organization for Scientific Research (NWO) via VICI grant 016.150.366 and via Gravity Program 024.001.035.

FundersFunder number
Marie Skłodowska‐Curie
Horizon 2020 Framework Programme754462
European Commission675179, H2020-MSCA-ITN-2015
Nederlandse Organisatie voor Wetenschappelijk Onderzoek016.150.366, 024.001.035

    Keywords

    • 14-3-3 proteins
    • cooperative effects
    • fragment-based drug discovery
    • imine chemistry
    • protein–protein interactions
    • Transcription Factor RelA/chemistry
    • Structure-Activity Relationship
    • Small Molecule Libraries/chemistry
    • Imines/chemistry
    • Protein Binding
    • 14-3-3 Proteins/chemistry
    • Molecular Structure
    • Protein Stability

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