Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 48, Pages 21520-21524Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202008585
Keywords
14-3-3 proteins; cooperative effects; fragment-based drug discovery; imine chemistry; protein-protein interactions
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Funding
- European Union through the TASPPI project (H2020-MSCA-ITN-2015) [675179]
- European Union through Eurotech Postdoctoral Fellow program [754462]
- European Union through Netherlands Organization for Scientific Research (NWO) via VICI grant [016.150.366]
- European Union through Netherlands Organization for Scientific Research (NWO) via Gravity Program [024.001.035]
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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-kappa B 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.
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