Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL

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, Andrew D. Hamilton

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Abstract

We describe a general method for the mimicry of one face of an α-helix based on a terphenyl scaffold that spatially projects functionality in a manner similar to that of two turns of an α-helix. The synthetic scaffold reduces the flexibility and molecular weight of the mimicked protein secondary structure. We have applied this design to the development of antagonists of the α-helix binding protein BCl-xL. Using a sequential synthetic strategy, we have prepared a library of terphenyl derivatives to mimic the helical region of the Bak BH3 domain that binds Bcl-xL. Fluorescence polarization assays were carried out to evaluate the ability of terphenyl derivatives to displace the Bcl-xL-bound Bak peptide. Terphenyl 14 exhibited good in vitro affinity with a Ki value of 0.114 μM. These terphenyl derivatives were more selective at disrupting the Bcl-xL/Bak over the HDM2/p53 interaction, which involves binding of the N-terminal α-helix of p53 to HDM2. Structural studies using NMR spectroscopy and computer-aided docking simulations suggested that the helix binding area on the surface of BCl-xL is the target for the synthetic ligands. Treatment of human embryonic kidney 293 (HEK293) cells with terphenyl derivatives resulted in the disruption of the binding of BCl-xL to Bax in intact cells.

Original languageEnglish (US)
Pages (from-to)10191-10196
Number of pages6
JournalJournal of the American Chemical Society
Volume127
Issue number29
DOIs
StatePublished - Jul 27 2005

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Yin, H., Lee, G. I., Sedey, K. A., Kutzki, O., Park, H. S., Orner, B. P., Ernst, J. T., Wang, H-G., Sebti, S. M., & Hamilton, A. D. (2005). Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL. Journal of the American Chemical Society, 127(29), 10191-10196. https://doi.org/10.1021/ja050122x