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

Research output: Contribution to journalArticle

173 Citations (Scopus)

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

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Molecular Weight
Molecular weight
Derivatives
Secondary Protein Structure
Fluorescence Polarization
Scaffolds
Libraries
Carrier Proteins
Magnetic Resonance Spectroscopy
Ligands
Kidney
Peptides
Nuclear magnetic resonance spectroscopy
Assays
Fluorescence
Polarization
Proteins
In Vitro Techniques

All Science Journal Classification (ASJC) codes

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

Cite this

Yin, H., Lee, G. I., Sedey, K. A., Kutzki, O., Park, H. S., Orner, B. P., ... 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
Yin, Hang ; Lee, Gui In ; Sedey, Kristine A. ; Kutzki, Olaf ; Park, Hyung Soon ; Orner, Brendan P. ; Ernst, Justin T. ; Wang, Hong-Gang ; Sebti, Said M. ; Hamilton, Andrew D. / Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL In: Journal of the American Chemical Society. 2005 ; Vol. 127, No. 29. pp. 10191-10196.
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Yin, H, Lee, GI, Sedey, KA, Kutzki, O, Park, HS, Orner, BP, Ernst, JT, Wang, H-G, Sebti, SM & Hamilton, AD 2005, 'Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL ', Journal of the American Chemical Society, vol. 127, no. 29, pp. 10191-10196. https://doi.org/10.1021/ja050122x

Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL . / Yin, Hang; Lee, Gui In; Sedey, Kristine A.; Kutzki, Olaf; Park, Hyung Soon; Orner, Brendan P.; Ernst, Justin T.; Wang, Hong-Gang; Sebti, Said M.; Hamilton, Andrew D.

In: Journal of the American Chemical Society, Vol. 127, No. 29, 27.07.2005, p. 10191-10196.

Research output: Contribution to journalArticle

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T1 - Terphenyl-based Bak BH3 α-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL

AU - Yin, Hang

AU - Lee, Gui In

AU - Sedey, Kristine A.

AU - Kutzki, Olaf

AU - Park, Hyung Soon

AU - Orner, Brendan P.

AU - Ernst, Justin T.

AU - Wang, Hong-Gang

AU - Sebti, Said M.

AU - Hamilton, Andrew D.

PY - 2005/7/27

Y1 - 2005/7/27

N2 - 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.

AB - 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.

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