A rapid library screen for tailoring beta-peptide structure and function
Joshua Kritzer, Nathan W. Luedtke,
Elizabeth A. Harker, and Alanna Schepartz
Abstract
Recently we described a b-decapeptide (b53-1)
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 b53-1
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 b53-1 analogues possessing
diversity along a non-recognition face might contain molecules possessing
greater affinity for hDM2. Here we describe (1) b-peptide
synthesis protocols that produce high quality one-bead-one-b-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 b53-1
analogues with improved structural and functional properties.
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