Helical β-peptide inhibitors of the p53-hDM2 interaction

hDM2 is recognized in vivo by a short α-helix within the p53 trans-activation domain (p53AD). Disruption of the p53·hDM2 interaction is an important goal for cancer therapy. A functional epitope comprised of three residues on one face of the p53AD helix (F19, W23, and L26) contributes heavily to the binding free energy. We hypothesized that the p53AD functional epitope would be recapitulated if the side chains of F19, W23, and L26 were presented at successive positions three residues apart on a stabilized β3-peptide 14-helix. Here, we report a set of β3-peptides that possess significant 14-helix structure in water; one recognizes a cleft on the surface of hDM2 with nanomolar affinity. The strategy for β3-peptide design that we describe is general and may have advantages over one in which individual or multiple β-amino acid substitutions are introduced into a functional α-peptide, because it is based on homology at the level of secondary structure, not primary sequence. Copyright © 2004 American Chemical Society.