A protein tertiary structure mimetic modulator of the Hippo signalling pathway

Hélène Adihou, Ranganath Gopalakrishnan, Tim Förster, Stéphanie M. Guéret, Raphael Gasper, Stefan Geschwindner, Carmen Carrillo García, Hacer Karatas, Ajaybabu V. Pobbati, Mercedes Vazquez‐Chantada, Paul Davey, Carola M. Wassvik, Jeremy Kah Sheng Pang, Boon Seng Soh, Wanjin Hong, Elisabetta Chiarparin, Dennis Schade, Alleyn T. Plowright, Eric Valeur, Malin Lemurell, Tom N. Grossmann () and Herbert Waldmann ()
Additional contact information
Hélène Adihou: AstraZeneca
Ranganath Gopalakrishnan: AstraZeneca
Tim Förster: AstraZeneca-MPI Satellite Unit
Stéphanie M. Guéret: AstraZeneca
Raphael Gasper: Max Planck Institute for Molecular Physiology
Stefan Geschwindner: AstraZeneca
Carmen Carrillo García: Christian-Albrechts-University of Kiel
Hacer Karatas: Max Planck Institute for Molecular Physiology
Ajaybabu V. Pobbati: A*STAR Institute of Molecular and Cell Biology
Mercedes Vazquez‐Chantada: AstraZeneca
Paul Davey: AstraZeneca
Carola M. Wassvik: AstraZeneca
Jeremy Kah Sheng Pang: Disease Modelling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology
Boon Seng Soh: Disease Modelling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology
Wanjin Hong: A*STAR Institute of Molecular and Cell Biology
Elisabetta Chiarparin: AstraZeneca
Dennis Schade: Christian-Albrechts-University of Kiel
Alleyn T. Plowright: AstraZeneca
Eric Valeur: AstraZeneca
Malin Lemurell: AstraZeneca
Tom N. Grossmann: VU University Amsterdam
Herbert Waldmann: Max Planck Institute for Molecular Physiology

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19224-8

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