Development of a potent Bcl-x(L) antagonist based on alpha-helix mimicry |
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Authors: | Kutzki Olaf Park Hyung Soon Ernst Justin T Orner Brendan P Yin Hang Hamilton Andrew D |
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Institution: | Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8107, USA. |
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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 alpha-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an alpha-helix, we designed mimics of the pro-apoptotic alpha-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. |
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