title: Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
abstract: 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(50)=125 microM), 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 1,000 times higher (IC(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 A 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.
authors.affiliation: Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Rudi
authors.initials: R
authors.lastname: Fasan
authors.forename: Ricardo L A
authors.initials: RL
authors.lastname: Dias
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moehle
authors.forename: Oliver
authors.initials: O
authors.lastname: Zerbe
authors.forename: Daniel
authors.initials: D
authors.lastname: Obrecht
authors.forename: Peer R E
authors.initials: PR
authors.lastname: Mittl
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D003460:Crystallization; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D008958:Models, Molecular; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D000939:Epitopes; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2