Title :

Stabilizer-Guided Inhibition of Protein-Protein Interactions

Author(s) :

Milroy, Lech-Gustav [Auteur]
Technische Universiteit Eindhoven [TU/e]
Bartel, Maria [Auteur]
Technische Universiteit Eindhoven [TU/e]
Henen, Morkos A. [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Leysen, Seppe [Auteur]
Technische Universiteit Eindhoven [TU/e]
Adriaans, Joris M. C. [Auteur]
Technische Universiteit Eindhoven [TU/e]
Brunsveld, Luc [Auteur]
Technische Universiteit Eindhoven [TU/e]
Landrieu, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Ottmann, Christian [Auteur]
Technische Universiteit Eindhoven [TU/e]

Journal title :

Angewandte Chemie International Edition

Volume number :

54

Pages :

15720-15724

Publication date :

2015-12-21

ISSN :

14337851

English keyword(s) :

Drug discovery
Peptide inhibitors
Protein-protein interactions
Structure-guided design

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different ...
Show more >The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs.Show less >

Language :

Anglais

Audience :

Non spécifiée

ANR Project :

Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

RMN et interactions moléculaires

Submission date :

2020-02-12T15:44:53Z
2021-04-28T09:16:55Z