A Rapid Library Screen for Tailoring β-Peptide Structure and Function

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Abstract
Recently we described a β-decapeptide (β 53 - 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 β 53 - 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 β 53 - 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 β 53 - 1 analogues with improved structural and functional properties.