Stabilizer-Guided Inhibition of Protein-Protein Interactions

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–st...

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Bibliographic Details
Published in:	Angewandte Chemie Vol. 127; no. 52; pp. 15946 - 15950
Main Authors:	Milroy, Lech-Gustav, Bartel, Maria, Henen, Morkos A., Leysen, Seppe, Adriaans, Joris M. C., Brunsveld, Luc, Landrieu, Isabelle, Ottmann, Christian
Format:	Journal Article
Language:	English German
Published:	Weinheim WILEY-VCH Verlag 21.12.2015 WILEY‐VCH Verlag Wiley Subscription Services, Inc
Subjects:	Adapter proteins Adapters Alzheimer's disease Binding Chemistry Crystallography Inhibitors Magnetic resonance spectroscopy Modulators Neurodegenerative diseases NMR NMR spectroscopy Nuclear magnetic resonance Peptidinhibitoren Protein interaction Protein-Protein-Wechselwirkungen Proteins Strukturgeleitetes Design Tau protein Therapeutic targets Vices Wirkstoff-Forschung X-rays
ISSN:	0044-8249, 1521-3757
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Summary:	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. Die Entwicklung eines Inhibitors von Protein‐Protein‐Wechselwirkungen wurde von der Kokristallstruktur eines Protein‐Stabilisator‐Komplexes geleitet. Der wirksamste Inhibitor der Bindung von 14‐3‐3 an das phosphorylierte Volllängen‐Tau‐Protein wurde biochemisch und biophysikalisch analysiert. Er hat eine neuartige molekulare Struktur, die spezifisch in die Inhibitor‐Stabilisator‐Schnittstelle von 14‐3‐3 bindet.
Bibliography:	istex:F6C52F965C2D782E692823F7BA4756AA3F9E5556 CNRS Pasteur Institute of Lille TGE RMN THC - No. FR-3050 ArticleID:ANGE201507976 Marie Curie Action - No. PIAPP-GA-2011-286418 14-3-3Stabs; No. ANR-11-LABX-009 European Community North of France Region Netherlands Organization for Scientific Research - No. 024.001.035 Lille University ark:/67375/WNG-ZR14HFS2-H French Research Ministry ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0044-8249 1521-3757
DOI:	10.1002/ange.201507976