A rapid library screen for tailoring β-peptide structure and function

Recently we described a β-decapeptide (β53-1) 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 β53-1 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 β53-1 analogues possessing diversity along a nonrecognition face might contain molecules possessing greater affinity for hDM2. Here we describe (1) β-peptide synthesis protocols that produce high quality one-bead-one-β-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 β53-1 analogues with improved structural and functional properties. Copyright © 2005 American Chemical Society.