Multivalent ligands with tailor-made anion binding motif as stabilizers of protein–protein interactions

Lina Bartsch; Maria Bartel; Alba Gigante; Javier Iglesias-Fernández; Yasser B. Ruiz-Blanco; Christine Beuck; Jeroen Briels; Niklas Toetsch; Peter Bayer; Elsa Sanchez-Garcia; Christian Ottmann; Carsten Schmuck

doi:10.1002/cbic.201900288

Multivalent ligands with tailor-made anion binding motif as stabilizers of protein–protein interactions

Lina Bartsch, Maria Bartel, Alba Gigante, Javier Iglesias-Fernández, Yasser B. Ruiz-Blanco, Christine Beuck, Jeroen Briels, Niklas Toetsch, Peter Bayer, Elsa Sanchez-Garcia, Christian Ottmann (Corresponding author), Carsten Schmuck

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

12 Citations (Scopus)

Abstract

Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.

Original language	English
Pages (from-to)	2921-2926
Number of pages	6
Journal	ChemBioChem
Volume	20
Issue number	23
Early online date	9 Jun 2019
DOIs	https://doi.org/10.1002/cbic.201900288
Publication status	Published - 2 Dec 2019

Keywords

14-3-3 proteins
C-Raf
guanidiniocarbonylpyrrol
protein–protein interactions
stabilizers
Tau
protein-protein interactions

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10.1002/cbic.201900288

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Bartsch, L., Bartel, M., Gigante, A., Iglesias-Fernández, J., Ruiz-Blanco, Y. B., Beuck, C., Briels, J., Toetsch, N., Bayer, P., Sanchez-Garcia, E., Ottmann, C., & Schmuck, C. (2019). Multivalent ligands with tailor-made anion binding motif as stabilizers of protein–protein interactions. ChemBioChem, 20(23), 2921-2926. Advance online publication. https://doi.org/10.1002/cbic.201900288

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abstract = "Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.",

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AU - Bartsch, Lina

AU - Bartel, Maria

AU - Gigante, Alba

AU - Iglesias-Fernández, Javier

AU - Ruiz-Blanco, Yasser B.

AU - Beuck, Christine

AU - Briels, Jeroen

AU - Toetsch, Niklas

AU - Bayer, Peter

AU - Sanchez-Garcia, Elsa

AU - Ottmann, Christian

AU - Schmuck, Carsten

PY - 2019/12/2

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AB - Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.

KW - 14-3-3 proteins

KW - C-Raf

KW - guanidiniocarbonylpyrrol

KW - protein–protein interactions

KW - stabilizers

KW - Tau

KW - protein-protein interactions

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JO - ChemBioChem

JF - ChemBioChem

IS - 23

ER -

Multivalent ligands with tailor-made anion binding motif as stabilizers of protein–protein interactions

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Keywords

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