Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix.
We report the design of side-chain-to-tail linked organo-peptide hybrids incorporating an α-helical protein-binding motif. Using this strategy, macrocyclic inhibitors of the p53:HDM2 interaction displaying dual specificity against the HDMX homolog as well as increased proteolytic stability could be obtained.
Department of Chemistry, University of Rochester, Rochester, NY, USA. fasan@chem.rochester.edu.
Jessica M
JM
Smith
John R
JR
Frost
Rudi
R
Fasan
D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047028:Macrocyclic Compounds; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2