These authors contributed equally to this work.
Structure–Activity Studies in a Family of β-Hairpin Protein Epitope Mimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction
Version of Record online: 1 MAR 2006
Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 7, Issue 3, pages 515–526, March 6, 2006
How to Cite
Fasan, R., Dias, R. L. A., Moehle, K., Zerbe, O., Obrecht, D., Mittl, P. R. E., Grütter, M. G. and Robinson, J. A. (2006), Structure–Activity Studies in a Family of β-Hairpin Protein Epitope Mimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction. ChemBioChem, 7: 515–526. doi: 10.1002/cbic.200500452
- Issue online: 1 MAR 2006
- Version of Record online: 1 MAR 2006
- Manuscript Received: 2 NOV 2005
- peptide nucleic acids;
- protein–protein interactions;
- secondary structure
Inhibitors of the interaction between the p53 tumor-suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing β-hairpin peptidomimetics of the α-helical epitope on p53 that would bind tightly to the p53-binding site on HDM2. The β-hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead β-hairpin mimetic, with a weak inhibitory activity (IC50=125 μM), was optimized to afford cyclo-(L-Pro-Phe-Glu-6ClTrp-Leu-Asp-Trp-Glu-Phe-D-Pro) (where 6ClTrp=L-6-chlorotryptophan), which has an affinity almost 1000 times higher (IC50=140 nM). In this work, insights into the origins of this affinity maturation based on structure–activity studies and an X-ray crystal structure of the inhibitor/HDM2(residues 17–125) complex at 1.4 Å resolution are described. The crystal structure confirms the β-hairpin conformation of the bound ligand, and also reveals that a significant component of the affinity increase arises through new aromatic/aromatic stacking interactions between side chains around the hairpin and groups on the surface of HDM2.