Identification of she Src homology 2 domain-binding peptoid-peptide hybrids

Won Jun Choi, Sung Eun Kim, Andrew G. Stephen, Iwona Weidlich, Alessio Giubellino, Fa Liu, Karen M. Worthy, Lakshman Bindu, Matthew J. Fivash, Marc C. Nicklaus, Donald P. Bottaro, Robert J. Fisher, Terrence R. Burke

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9 Scopus citations


A fluorescence anisotropy (FA) competition-based Shc Src homology 2 (SH2) domain-binding was established using the high affinity fluorescein isothiocyanate (FITC) containing peptide, FITC-NH-(CH 2) 4-CO-pY-Q- G-L-S-amide (8; K d = 0.35 μM). Examination of a series of open-chain bis-alkenylamide containing peptides, prepared as ring-closing metathesis precursors, showed that the highest affinities were obtained by replacement of the original Gly residue with N α- substituted Gly (NSG) "peptoid" residues. This provided peptoid-peptide hybrids of the form "Ac-pY-Q-[NSG]-L-amide." Depending on the NSG substituent, certain of these hybrids exhibited up to 40-fold higher Shc SH2 domain-binding affinity than the parent Gly-containing peptide (IC 50 = 248 μM) (for example, for N-homoallyl analogue 50,IC 50 = 6 μM). To our knowledge, this work represents the first successful example of the application of peptoid-peptide hybrids in the design of SH2 domain-binding antagonists. These results could provide a foundation for further structural optimization of Shc SH2 domain-binding peptide mimetics.

Original languageEnglish (US)
Pages (from-to)1612-1618
Number of pages7
JournalJournal of medicinal chemistry
Issue number6
StatePublished - Mar 26 2009


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