当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction.

Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction.

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 affinity and metabolic stability relative to wild-type and linear BCL9 peptides. This study lays the foundation for further optimization of these triazole-stapled BCL9 peptides as potent, metabolically stable, and cell-permeable inhibitors to target the β-catenin and BCL9 interaction.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kawamoto SA,Coleska A,Ran X,Yi H,Yang CY,Wang S

doi

10.1021/jm201125d

subject

Has Abstract

pub_date

2012-02-09 00:00:00

pages

1137-46

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

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