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A protein tertiary structure mimetic modulator of the Hippo signalling pathway

Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but h...

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Autores principales: Adihou, Hélène, Gopalakrishnan, Ranganath, Förster, Tim, Guéret, Stéphanie M., Gasper, Raphael, Geschwindner, Stefan, Carrillo García, Carmen, Karatas, Hacer, Pobbati, Ajaybabu V., Vazquez‐Chantada, Mercedes, Davey, Paul, Wassvik, Carola M., Pang, Jeremy Kah Sheng, Soh, Boon Seng, Hong, Wanjin, Chiarparin, Elisabetta, Schade, Dennis, Plowright, Alleyn T., Valeur, Eric, Lemurell, Malin, Grossmann, Tom N., Waldmann, Herbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920/
https://www.ncbi.nlm.nih.gov/pubmed/33110077
http://dx.doi.org/10.1038/s41467-020-19224-8
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author Adihou, Hélène
Gopalakrishnan, Ranganath
Förster, Tim
Guéret, Stéphanie M.
Gasper, Raphael
Geschwindner, Stefan
Carrillo García, Carmen
Karatas, Hacer
Pobbati, Ajaybabu V.
Vazquez‐Chantada, Mercedes
Davey, Paul
Wassvik, Carola M.
Pang, Jeremy Kah Sheng
Soh, Boon Seng
Hong, Wanjin
Chiarparin, Elisabetta
Schade, Dennis
Plowright, Alleyn T.
Valeur, Eric
Lemurell, Malin
Grossmann, Tom N.
Waldmann, Herbert
author_facet Adihou, Hélène
Gopalakrishnan, Ranganath
Förster, Tim
Guéret, Stéphanie M.
Gasper, Raphael
Geschwindner, Stefan
Carrillo García, Carmen
Karatas, Hacer
Pobbati, Ajaybabu V.
Vazquez‐Chantada, Mercedes
Davey, Paul
Wassvik, Carola M.
Pang, Jeremy Kah Sheng
Soh, Boon Seng
Hong, Wanjin
Chiarparin, Elisabetta
Schade, Dennis
Plowright, Alleyn T.
Valeur, Eric
Lemurell, Malin
Grossmann, Tom N.
Waldmann, Herbert
author_sort Adihou, Hélène
collection PubMed
description Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.
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spelling pubmed-75919202020-11-10 A protein tertiary structure mimetic modulator of the Hippo signalling pathway Adihou, Hélène Gopalakrishnan, Ranganath Förster, Tim Guéret, Stéphanie M. Gasper, Raphael Geschwindner, Stefan Carrillo García, Carmen Karatas, Hacer Pobbati, Ajaybabu V. Vazquez‐Chantada, Mercedes Davey, Paul Wassvik, Carola M. Pang, Jeremy Kah Sheng Soh, Boon Seng Hong, Wanjin Chiarparin, Elisabetta Schade, Dennis Plowright, Alleyn T. Valeur, Eric Lemurell, Malin Grossmann, Tom N. Waldmann, Herbert Nat Commun Article Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators. Nature Publishing Group UK 2020-10-27 /pmc/articles/PMC7591920/ /pubmed/33110077 http://dx.doi.org/10.1038/s41467-020-19224-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Adihou, Hélène
Gopalakrishnan, Ranganath
Förster, Tim
Guéret, Stéphanie M.
Gasper, Raphael
Geschwindner, Stefan
Carrillo García, Carmen
Karatas, Hacer
Pobbati, Ajaybabu V.
Vazquez‐Chantada, Mercedes
Davey, Paul
Wassvik, Carola M.
Pang, Jeremy Kah Sheng
Soh, Boon Seng
Hong, Wanjin
Chiarparin, Elisabetta
Schade, Dennis
Plowright, Alleyn T.
Valeur, Eric
Lemurell, Malin
Grossmann, Tom N.
Waldmann, Herbert
A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title_full A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title_fullStr A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title_full_unstemmed A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title_short A protein tertiary structure mimetic modulator of the Hippo signalling pathway
title_sort protein tertiary structure mimetic modulator of the hippo signalling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920/
https://www.ncbi.nlm.nih.gov/pubmed/33110077
http://dx.doi.org/10.1038/s41467-020-19224-8
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