Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering.

Autor: Wolter M; Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands., Valenti D; Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Cossar PJ; Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands., Levy LM; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Hristeva S; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Genski T; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Hoffmann T; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Brunsveld L; Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands., Tzalis D; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227, Dortmund, Germany., Ottmann C; Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.; Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117, Essen, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Nov 23; Vol. 59 (48), pp. 21520-21524. Date of Electronic Publication: 2020 Sep 25.
DOI: 10.1002/anie.202008585
Abstrakt: 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.
(© 2020 The Authors. Published by Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: