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An exploration of chemical properties required for cooperative stabilization of the 14-3-3 interaction with NF-κB—utilizing a reversible covalent tethering approach

DOI: 10.1021/acs.jmedchem.1c00401 DOI Help

Authors: Madita Wolter (Eindhoven University of Technology) , Dario Valenti (Eindhoven University of Technology; Taros Chemicals GmbH & Co) , Peter J. Cossar (Eindhoven University of Technology) , Stanimira Hristeva (Taros Chemicals GmbH & Co) , Laura M. Levy (Taros Chemicals GmbH & Co) , Thorsten Genski (Taros Chemicals GmbH & Co) , Torsten Hoffmann (Taros Chemicals GmbH & Co) , Luc Brunsveld (Eindhoven University of Technology) , Dimitrios Tzalis (Taros Chemicals GmbH & Co) , Christian Ottmann (Technische Universiteit Eindhoven)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: June 2021

Open Access Open Access

Abstract: Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

Journal Keywords: Peptides and proteins; Assays; Hydrophobicity; Stabilization; Titration

Subject Areas: Chemistry, Medicine, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 07/06/2021 09:16

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)