title: A rapid library screen for tailoring beta-peptide structure and function.
abstract: Recently we described a beta-decapeptide (beta53-1) that folds into a 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and inhibits the interaction of hDM2 with a peptide derived from the activation domain of p53 (p53AD). The solution structure of beta53-1 in CD3OH revealed an unexpected C-terminal unwinding that staggers the side chains comprising the hDM2 recognition epitope to better mimic those of p53AD. The structure-function relationship implied by this distortion suggested that a library of beta53-1 analogues possessing diversity along a nonrecognition face might contain molecules possessing greater affinity for hDM2. Here we describe (1) beta-peptide synthesis protocols that produce high quality one-bead-one-beta-peptide libraries suitable for on-bead screening without purification, (2) a versatile, scalable on-bead screen, and (3) a simple tandem mass spectrometry (MS/MS) decoding method. Using this procedure, we identified beta53-1 analogues with improved structural and functional properties.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kritzer
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Luedtke
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Harker
authors.forename: Alanna
authors.initials: A
authors.lastname: Schepartz
mesh_terms: D008024:Ligands; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019151:Peptide Library; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2