Helical beta-peptide inhibitors of the p53-hDM2 interaction.
hDM2 is recognized in vivo by a short alpha-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 beta3-peptide 14-helix. Here, we report a set of beta3-peptides that possess significant 14-helix structure in water; one recognizes a cleft on the surface of hDM2 with nanomolar affinity. The strategy for beta3-peptide design that we describe is general and may have advantages over one in which individual or multiple beta-amino acid substitutions are introduced into a functional alpha-peptide, because it is based on homology at the level of secondary structure, not primary sequence.
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Joshua A
JA
Kritzer
James D
JD
Lear
Michael E
ME
Hodsdon
Alanna
A
Schepartz
D002942:Circular Dichroism; D005454:Fluorescence Polarization; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2