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

J Med Chem. 2009 Mar 26;52(6):1612-8. doi: 10.1021/jm800789h.


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-(CH2)4-CO-pY-Q-G-L-S-amide (8; Kd = 0.35 microM). 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 alpha-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 (IC50 = 248 microM) (for example, for N-homoallyl analogue 50, IC50 = 6 microM). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Fluorescein-5-isothiocyanate / chemistry
  • Fluorescence Polarization
  • Magnetic Resonance Spectroscopy
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / metabolism*
  • Peptoids / chemistry
  • Peptoids / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • src Homology Domains*


  • Peptides
  • Peptoids
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • Fluorescein-5-isothiocyanate