Structure-Activity Studies in a Family of [beta]-Hairpin Protein Epitope Mimetic Inhibitors of the p53-HDM2 Protein-Protein Interaction

• Published in: Chembiochem : a European journal of chemical biology Vol. 7; no. 3; pp. 515 - 526
• Main Authors: Fasan, Rudi, Dias, Ricardo LA, Moehle, Kerstin, Zerbe, Oliver, Obrecht, Daniel, Mittl, Peer RE, Gruetter, Markus G, Robinson, John A
• Format: Journal Article
• Language: English
• Published: 24.01.2006
• DOI: 10.1002/cbic.200500452
• ISSN: 1439-4227

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 [beta]-hairpin peptidomimetics of the [alpha]-helical epitope on p53 that would bind tightly to the p53-binding site on HDM2. The [beta]-hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead [beta]- hairpin mimetic, with a weak inhibitory activity (IC sub(50)=125 [mu]M), 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 (IC sub(50)=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 Aa resolution are described. The crystal structure confirms the [beta]-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.