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

Autor: Yeste-Vázquez A; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Paulussen FM; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Wendt M; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Klintrot R; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Schulte C; Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of, Wuerzburg, Germany., Wallraven K; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., van Gijzel L; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Simeonov B; Department of Neurosurgery, Amsterdam UMC, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Biology, Amsterdam UMC, Amsterdam, The Netherlands., van der Gaag M; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Department of Neurosurgery, Amsterdam UMC, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Biology, Amsterdam UMC, Amsterdam, The Netherlands., Gerber A; Department of Neurosurgery, Amsterdam UMC, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Biology, Amsterdam UMC, Amsterdam, The Netherlands., Maric HM; Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of, Wuerzburg, Germany., Hennig S; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands., Grossmann TN; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Nov 18; Vol. 63 (47), pp. e202411749. Date of Electronic Publication: 2024 Oct 21.
DOI: 10.1002/anie.202411749
Abstrakt: 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.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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