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 |
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.
Funders | Funder number |
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Marie Skłodowska‐Curie | |
European Union's Horizon 2020 - Research and Innovation Framework Programme | 754462 |
European Commission | 675179, H2020-MSCA-ITN-2015 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 016.150.366, 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