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 language | English |
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Pages (from-to) | 21520-21524 |
Number of pages | 5 |
Journal | Angewandte Chemie - International Edition |
Volume | 59 |
Issue number | 48 |
Early online date | 20 Aug 2020 |
DOIs | |
Publication status | Published - 23 Nov 2020 |
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