Development of a Potent Bcl-xL Antagonist Based on -Helix Mimicry
详细信息 查看全文
- 作者：Olaf Kutzki ; Hyung Soon Park ; Justin T. Ernst ; Brendan P. Orner ; Hang Yin ; and Andrew D. Hamilton
- 刊名：Journal of the American Chemical Society
- 出版年：2002
- 出版时间：October 9, 2002
- 年：2002
- 卷：124
- 期：40
- 页码：11838 - 11839
- 全文大小：215K
- 年卷期：v.124,no.40(October 9, 2002)
- ISSN：1520-5126
文摘
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 
-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an -helix, we designed mimics of the pro-apoptotic -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.
-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an -helix, we designed mimics of the pro-apoptotic -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.