Development of a potent Bcl-xL antagonist based on α-helix mimicry

Olaf Kutzki, Hyung Soon Park, Justin T. Ernst, Brendan P. Orner, Hang Yin, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

The rational design of low-molecular weight ligands that disrupt protein-protein interactions is still a challenging goal in medicinal chemistry. Our approach to this problem involves the design of molecular scaffolds that mimic the surface functionality projected along one face of an α-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an α-helix, we designed mimics of the pro-apoptotic α-helical Bak-peptide as inhibitors of the Bak/Bcl-xL interaction. This led to the development of a potent Bcl-xL antagonist (KD = 114 nM), whose binding affinity for Bcl-xL was assessed by a fluorescence polarization assay. To determine the binding site of the developed inhibitor we used docking studies and an HSQC-NMR experiment with 15N-labeled Bcl-xL protein. These studies suggest that the inhibitor is binding in the same hydrophobic cleft as the Bak- and Bad-peptides.

Original languageEnglish (US)
Pages (from-to)11838-11839
Number of pages2
JournalJournal of the American Chemical Society
Volume124
Issue number40
DOIs
StatePublished - Oct 9 2002

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Proteins
Scaffolds
Peptides
Fluorescence Polarization
Pharmaceutical Chemistry
Binding sites
Conformations
Assays
Molecular Weight
Fluorescence
Molecular weight
Binding Sites
Ligands
Nuclear magnetic resonance
Polarization
Experiments

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Development of a potent Bcl-xL antagonist based on α-helix mimicry. / Kutzki, Olaf; Park, Hyung Soon; Ernst, Justin T.; Orner, Brendan P.; Yin, Hang; Hamilton, Andrew.

In: Journal of the American Chemical Society, Vol. 124, No. 40, 09.10.2002, p. 11838-11839.

Research output: Contribution to journalArticle

Kutzki, Olaf ; Park, Hyung Soon ; Ernst, Justin T. ; Orner, Brendan P. ; Yin, Hang ; Hamilton, Andrew. / Development of a potent Bcl-xL antagonist based on α-helix mimicry. In: Journal of the American Chemical Society. 2002 ; Vol. 124, No. 40. pp. 11838-11839.
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