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Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling
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 for example, as inhibitors of protein–protein interactions (PPIs). Even though β‐sheets participat...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252567/ https://www.ncbi.nlm.nih.gov/pubmed/33783110 http://dx.doi.org/10.1002/anie.202102082 |
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author | Wendt, Mathias Bellavita, Rosa Gerber, Alan Efrém, Nina‐Louisa van Ramshorst, Thirza Pearce, Nicholas M. Davey, Paul R. J. Everard, Isabel Vazquez‐Chantada, Mercedes Chiarparin, Elisabetta Grieco, Paolo Hennig, Sven Grossmann, Tom N. |
author_facet | Wendt, Mathias Bellavita, Rosa Gerber, Alan Efrém, Nina‐Louisa van Ramshorst, Thirza Pearce, Nicholas M. Davey, Paul R. J. Everard, Isabel Vazquez‐Chantada, Mercedes Chiarparin, Elisabetta Grieco, Paolo Hennig, Sven Grossmann, Tom N. |
author_sort | Wendt, Mathias |
collection | PubMed |
description | 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 for example, 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. |
format | Online Article Text |
id | pubmed-8252567 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82525672021-07-09 Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling Wendt, Mathias Bellavita, Rosa Gerber, Alan Efrém, Nina‐Louisa van Ramshorst, Thirza Pearce, Nicholas M. Davey, Paul R. J. Everard, Isabel Vazquez‐Chantada, Mercedes Chiarparin, Elisabetta Grieco, Paolo Hennig, Sven Grossmann, Tom N. Angew Chem Int Ed Engl Research Articles 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 for example, 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. John Wiley and Sons Inc. 2021-05-05 2021-06-14 /pmc/articles/PMC8252567/ /pubmed/33783110 http://dx.doi.org/10.1002/anie.202102082 Text en © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Wendt, Mathias Bellavita, Rosa Gerber, Alan Efrém, Nina‐Louisa van Ramshorst, Thirza Pearce, Nicholas M. Davey, Paul R. J. Everard, Isabel Vazquez‐Chantada, Mercedes Chiarparin, Elisabetta Grieco, Paolo Hennig, Sven Grossmann, Tom N. Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title | Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title_full | Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title_fullStr | Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title_full_unstemmed | Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title_short | Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling |
title_sort | bicyclic β‐sheet mimetics that target the transcriptional coactivator β‐catenin and inhibit wnt signaling |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252567/ https://www.ncbi.nlm.nih.gov/pubmed/33783110 http://dx.doi.org/10.1002/anie.202102082 |
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