Bicyclic β‐sheet mimetics that target the transcriptional coactivator β‑catenin and inhibit Wnt signaling

DOI: 10.1002/anie.202102082

Authors: Mathias Wendt (Vrije Universiteit Amsterdam) , Rosa Bellavita (Vrije Universiteit Amsterdam) , Alan Gerber (Vrije Universiteit Amsterdam) , Nina-Louisa Efrém (Vrije Universiteit Amsterdam) , Thirza Van Ramshorst (Vrije Universiteit Amsterdam) , Nicholas M. Pearce (Vrije Universiteit Amsterdam) , Paul R. J. Davey (AstraZeneca) , Isabel Everard (AstraZeneca) , Mercedes Vazquez-Chantada (AstraZeneca) , Elisabetta Chiarpari (AstraZeneca) , Paolo Grieco (University of Naples Federico II) , Sven Hennig (Vrije Universiteit Amsterdam) , Tom N. Grossmann (Vrije Universiteit Amsterdam)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 19800

Abstract: Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied e.g. as inhibitors of protein‐protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs.

Journal Keywords: cell-penetrating peptides; macrocycles; peptidomimetics; protein-protein interaction; Thioether crosslink; Wnt Signaling;

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


Instruments: I04-Macromolecular Crystallography

Added On: 30/03/2021 15:19

Documents:
anie.202102082.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)