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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Veröffentlicht in:	Angewandte Chemie International Edition Jg. 54; H. 52; S. 15720 - 15724
Hauptverfasser:	Milroy, Lech-Gustav, Bartel, Maria, Henen, Morkos A., Leysen, Seppe, Adriaans, Joris M. C., Brunsveld, Luc, Landrieu, Isabelle, Ottmann, Christian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Weinheim WILEY-VCH Verlag 21.12.2015 WILEY‐VCH Verlag Wiley Wiley Subscription Services, Inc Wiley-VCH Verlag
Ausgabe:	International ed. in English
Schlagworte:	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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Abstract	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.
AbstractList	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 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. 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 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 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 Xray crystallographic data from both stabilizer and inhibitor cocrystal 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.
Author	Leysen, Seppe Adriaans, Joris M. C. Bartel, Maria Landrieu, Isabelle Milroy, Lech-Gustav Brunsveld, Luc Ottmann, Christian Henen, Morkos A.
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Keywords	drug discovery INTERFACE PHOSPHORYLATION MICROTUBULES SMALL-MOLECULE INHIBITORS peptide inhibitors TAU BINDING protein-protein interactions structure-guided design
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Snippet	The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated... The discovery of novel protein-protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated...
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SubjectTerms	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
Title	Stabilizer-Guided Inhibition of Protein-Protein Interactions
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