Structure‐Based Design of Bicyclic Helical Peptides That Target the Oncogene β‐Catenin

Abstract: The inhibition of intracellular protein‐protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co‐activator protein and oncogene β‐catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high‐affinity binders comprise only large molecular weight inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α‐helical β‐catenin‐binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a β‐catenin inhibitor with single‐digit micromolar activity in a cell‐based assay. This study sheds light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

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• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch

Verweise und Beziehungen

• Erschienen in: Structure‐Based Design of Bicyclic Helical Peptides That Target the Oncogene β‐Catenin ; day:21 ; month:10 ; year:2024 ; extent:9 ; Angewandte Chemie ; (21.10.2024) (gesamt 9)

Beteiligte, Orts- und Zeitangaben

• Urheber: Yeste‐Vázquez, Alejandro ; Paulussen, Felix M. ; Wendt, Mathias ; Klintrot, Rasmus ; Schulte, Clemens ; Wallraven, Kerstin ; van Gijzel, Lieke ; Simeonov, Boris ; van der Gaag, Maurice ; Gerber, Alan ; Maric, Hans M. ; Hennig, Sven ; Großmann, Tom N.

Weitere Informationen

• DOI: 10.1002/ange.202411749
• URN: urn:nbn:de:101:1-2410221411536.634126533746
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.