The design of novel protein ligands and inhibitors of protein– protein interactions is an important goal in post-genomic proteome analyses and in drug and vaccine discovery. Unfortunately, the design of synthetic molecules that target surface-exposed regions on folded proteins is presently difficult. Moreover, typical libraries of small “druglike” compounds have so far not been a fruitful source of protein–protein interaction inhibitors. One potential approach to such inhibitors arises through the design and synthesis of peptidomimetics that reproduce the conformational and electronic properties of functional native protein epitopes (so-called protein epitope mimetics (PEMs)). One supersecondary structure frequently found at natural protein– protein interfaces is the b-hairpin motif. Conceivably, bhairpin mimetics, just like the natural motifs in functional protein epitopes, may provide a robust presentation platform upon which the groups (e.g. side chains) essential for protein surface capture can be combined in a structurally defined yet malleable array. As an illustration of this approach and the robustness of the b-hairpin scaffold, we show here how bhairpin PEMs based on a naturally occurring a-helical peptide can be designed as inhibitors of the p53–HDM2 interaction. The p53 tumor suppressor, which is present at low concentrations in normal cells and at elevated levels in cells subject to stress, is regulated by its interaction with HDM2. The design of molecules that inhibit the interaction between p53 and HDM2 appears to be an attractive strategy for increasing p53 tumor-suppressor activity in tumor cells. The HDM2-binding domain on p53 is localized to a region at the N-terminus of the protein, from about residues 10–30. The p53-binding domain on HDM2 is also located at the Nterminus of this multidomain protein from residues 1–120. The structure of a complex formed between HDM2 (residues 17–125) and a p53-derived peptide (residues 15–29) has been determined by X-ray crystallography. The p53-derived peptide adopts a largely amphipathic a-helical backbone conformation, with the side chains of Phe19, Trp23, and Leu26 inserting into hydrophobic pockets on the surface of the HDM2 domain (Figure 1). The HDM2–p53 interface buries a total of 1498 = of surface in the complex, or about 690 = and 808 =, respectively, on each protein. Some of the few known p53–HDM2 inhibitors include the natural product chlorofusin, various linear peptides, and some chalcone derivatives. For the design of a p53 mimetic we noted that the distance between the Ca atoms of Phe19 and Trp23 on one face of the HDM2-bound p53 a-helix is close to the distance expected between the Ca atoms of two residues i and i+ 2 along one strand of a b-hairpin (see Figure 2). A designed hairpin