Fragment‐Based Stabilizers of Protein–Protein Interactions through Imine‐Based Tethering

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...

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Vydané v:	Angewandte Chemie International Edition Ročník 59; číslo 48; s. 21520 - 21524
Hlavní autori:	Wolter, Madita, Valenti, Dario, Cossar, Peter J., Levy, Laura M., Hristeva, Stanimira, Genski, Thorsten, Hoffmann, Torsten, Brunsveld, Luc, Tzalis, Dimitrios, Ottmann, Christian
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	WEINHEIM Wiley 23.11.2020 Wiley Subscription Services, Inc John Wiley and Sons Inc
Vydanie:	International ed. in English
Predmet:	14-3-3 proteins 14-3-3 Proteins - chemistry Adapter proteins Adapters Adhesives Chemistry Chemistry, Multidisciplinary Communication Communications cooperative effects Crystallography Drug development fragment-based drug discovery Fragments Glues imine chemistry Imines - chemistry Lysine Molecular Structure Optimization Peptides Physical Sciences Protein Binding Protein interaction Protein Stability Proteins protein–protein interactions Science & Technology Small Molecule Libraries - chemistry Stabilization Structure-Activity Relationship Tethering Transcription Factor RelA - chemistry 14-3-3 proteins fragment-based drug discovery DRUG DISCOVERY TARGETS imine chemistry cooperative effects protein-protein interactions
ISSN:	1433-7851, 1521-3773, 1521-3773
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Popis
Shrnutí:	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. A novel concept for optimizing orthosteric protein–protein interaction (PPI) stabilization is reported. Increasing interactions with the protein partner that contributes less to the composite binding pocket of the stabilizer (NF‐κB, red surface) results in increased stabilization, whereas further enhancing the interaction with the dominant partner protein (14‐3‐3, white surface) does not contribute to the stabilizing effect.
Bibliografia:	These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.202008585