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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Vydáno v:	Angewandte Chemie International Edition Ročník 54; číslo 52; s. 15720 - 15724
Hlavní autoři:	Milroy, Lech-Gustav, Bartel, Maria, Henen, Morkos A., Leysen, Seppe, Adriaans, Joris M. C., Brunsveld, Luc, Landrieu, Isabelle, Ottmann, Christian
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Weinheim WILEY-VCH Verlag 21.12.2015 WILEY‐VCH Verlag Wiley Wiley Subscription Services, Inc Wiley-VCH Verlag
Vydání:	International ed. in English
Témata:	14-3-3 Proteins - chemistry Adapter proteins Adapters Alzheimer's disease Biochemistry, Molecular Biology Chemical Sciences Chemistry Chemistry, Multidisciplinary Crystallography drug discovery Inhibitors Life Sciences Magnetic resonance spectroscopy Medicinal Chemistry Modulators Neurodegenerative diseases NMR NMR spectroscopy Nuclear magnetic resonance peptide inhibitors Physical Sciences Protein Binding Protein interaction protein-protein interactions Proteins Science & Technology Structural Biology structure-guided design Tau protein Therapeutic targets drug discovery INTERFACE PHOSPHORYLATION MICROTUBULES SMALL-MOLECULE INHIBITORS peptide inhibitors TAU BINDING protein-protein interactions structure-guided design
ISSN:	1433-7851, 1521-3773, 1521-3773
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Shrnutí:	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. The rational design of a protein–protein interaction inhibitor was guided by the co‐crystal structure of a protein–stabilizer complex and based on a non‐covalent tethering approach. The most potent inhibitor of the binding of 14‐3‐3 to phosphorylated full‐length Tau was biochemically and biophysically characterized and has a novel molecular structure that specifically targets the inhibitor–stabilizer interface of 14‐3‐3.
Bibliografie:	CNRS Pasteur Institute of Lille TGE RMN THC - No. FR-3050 Marie Curie Action - No. PIAPP-GA-2011-286418 14-3-3Stabs; No. ANR-11-LABX-009 European Community istex:2D2F1CCD90D14D902951EAEB82544134D5927E93 North of France Region Netherlands Organization for Scientific Research - No. 024.001.035 ArticleID:ANIE201507976 Lille University ark:/67375/WNG-6Q87R1JH-T French Research Ministry ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.201507976