Design of Triazole-Stapled BCL9 α-Helical Peptides to Target the β-Catenin/B-Cell CLL/lymphoma 9 (BCL9) Protein–Protein Interaction
TLDR
The use of the Huisgen 1,3-dipolar cycloaddition reaction to generate triazole-stapled BCL9 α-helical peptides is reported, which show a marked increase in helical character and an improvement in binding affinity and metabolic stability relative to wild-type and linear BCL 9 peptides.Abstract:
The interaction between β-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of β-catenin, is mediated by a helical segment from BCL9 and a large binding groove in β-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity of β-catenin. In this study, we report the use of the Huisgen 1,3-dipolar cycloaddition reaction to generate triazole-stapled BCL9 α-helical peptides. The high efficiency and mild conditions of this “click” reaction combined with the ease of synthesis of the necessary unnatural amino acids allows for facile synthesis of triazole-stapled peptides. We have performed extensive optimization of this approach and identified the optimal combinations of azido and alkynyl linkers necessary for stapling BCL9 helices. The unsymmetrical nature of the triazole staple also allowed the synthesis of double-stapled BCL9 peptides, which show a marked increase in helical character and an improvement in binding ...read more
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References
More filters
Journal ArticleDOI
Wnt signaling and cancer
TL;DR: In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
Journal ArticleDOI
The growing impact of click chemistry on drug discovery.
TL;DR: The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants.
Journal ArticleDOI
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
Loren D. Walensky,Andrew L. Kung,Andrew L. Kung,Iris Escher,Thomas J. Malia,Thomas J. Malia,Scott Barbuto,Renee D. Wright,Gerhard Wagner,Gregory L. Verdine,Stanley J. Korsmeyer +10 more
TL;DR: Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.
Journal ArticleDOI
An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides
Journal ArticleDOI
Direct inhibition of the NOTCH transcription factor complex
Raymond E. Moellering,Raymond E. Moellering,Melanie G. Cornejo,Tina N. Davis,Cristina Del Bianco,Jon C. Aster,Stephen C. Blacklow,Andrew L. Kung,D. Gary Gilliland,D. Gary Gilliland,Gregory L. Verdine,James E. Bradner,James E. Bradner +12 more
TL;DR: It is demonstrated that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex at a critical protein–protein interface in the NOTCH transactivation complex.
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