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Multivalent Ligands with Tailor‐Made Anion Binding Motif as Stabilizers of Protein–Protein Interactions
Author(s) -
Bartsch Lina,
Bartel Maria,
Gigante Alba,
IglesiasFernández Javier,
RuizBlanco Yasser B.,
Beuck Christine,
Briels Jeroen,
Toetsch Niklas,
Bayer Peter,
SanchezGarcia Elsa,
Ottmann Christian,
Schmuck Carsten
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900288
Subject(s) - chemistry , combinatorial chemistry , protein design , protein–protein interaction , biophysics , computational biology , biochemistry , nanotechnology , protein structure , biology , materials science
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.