Terphenyl-Based Bak BH3 -Helical Proteomimetics as Low-Molecular-Weight Antagonists of Bcl-xL

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• 作者：Hang Yin ; Gui-in Lee ; Kristine A. Sedey ; Olaf Kutzki ; Hyung Soon Park ; Brendan P. Orner ; Justin T. Ernst ; Hong-Gang Wang ; Said M. Sebti ; and Andrew D. Hamilton
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：July 27, 2005
• 年：2005
• 卷：127
• 期：29
• 页码：10191 - 10196
• 全文大小：413K
• 年卷期：v.127,no.29(July 27, 2005)
• ISSN：1520-5126

文摘

We describe a general method for the mimicry of one face of an mages/gifchars/alpha.gif" BORDER=0>-helix based on a terphenylscaffold that spatially projects functionality in a manner similar to that of two turns of an mages/gifchars/alpha.gif" BORDER=0>-helix. The syntheticscaffold reduces the flexibility and molecular weight of the mimicked protein secondary structure. We haveapplied this design to the development of antagonists of the mages/gifchars/alpha.gif" BORDER=0>-helix binding protein Bcl-x_L. Using a sequentialsynthetic strategy, we have prepared a library of terphenyl derivatives to mimic the helical region of theBak BH3 domain that binds Bcl-x_L. Fluorescence polarization assays were carried out to evaluate the abilityof terphenyl derivatives to displace the Bcl-x_L-bound Bak peptide. Terphenyl 14 exhibited good in vitroaffinity with a K_i value of 0.114 mages/entities/mgr.gif">M. These terphenyl derivatives were more selective at disrupting theBcl-x_L/Bak over the HDM2/p53 interaction, which involves binding of the N-terminal mages/gifchars/alpha.gif" BORDER=0>-helix of p53 to HDM2.Structural studies using NMR spectroscopy and computer-aided docking simulations suggested that thehelix binding area on the surface of Bcl-x_L is the target for the synthetic ligands. Treatment of humanembryonic kidney 293 (HEK293) cells with terphenyl derivatives resulted in the disruption of the binding ofBcl-x_L to Bax in intact cells.