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...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2004-08, Vol.126 (31), p.9468-9469
Main Authors: Kritzer, Joshua A, Lear, James D, Hodsdon, Michael E, Schepartz, Alanna
Format: Article
Language:English
Subjects:
Biological and medical sciences
Circular Dichroism
Fluorescence Polarization
Fundamental and applied biological sciences. Psychology
Humans
Interactions. Associations
Intermolecular phenomena
Models, Molecular
Molecular biophysics
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
Peptides - chemistry
Peptides - pharmacology
Protein Structure, Secondary
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p53 - antagonists & inhibitors
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja031625a