title: Terphenyl-Based Bak BH3 alpha-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL.
abstract: We describe a general method for the mimicry of one face of an alpha-helix based on a terphenyl scaffold that spatially projects functionality in a manner similar to that of two turns of an alpha-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 alpha-helix binding protein Bcl-x(L). 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-x(L). Fluorescence polarization assays were carried out to evaluate the ability of terphenyl derivatives to displace the Bcl-x(L)-bound Bak peptide. Terphenyl 14 exhibited good in vitro affinity with a K(i) value of 0.114 muM. These terphenyl derivatives were more selective at disrupting the Bcl-x(L)/Bak over the HDM2/p53 interaction, which involves binding of the N-terminal alpha-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-x(L) 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-x(L) to Bax in intact cells.
authors: Department of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut 06520-8107, USA.
authors: Hang
authors: H
authors: Yin
authors: Gui-In
authors: GI
authors: Lee
authors: Kristine A
authors: KA
authors: Sedey
authors: Olaf
authors: O
authors: Kutzki
authors: Hyung Soon
authors: HS
authors: Park
authors: Brendan P
authors: BP
authors: Orner
authors: Justin T
authors: JT
authors: Ernst
authors: Hong-Gang
authors: HG
authors: Wang
authors: Said M
authors: SM
authors: Sebti
authors: Andrew D
authors: AD
authors: Hamilton
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C474007:Bax protein (53-86); D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013730:Terphenyl Compounds; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein