title: Identification of Shc Src homology 2 domain-binding peptoid-peptide hybrids.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Stephen
authors.forename: Iwona
authors.initials: I
authors.lastname: Weidlich
authors.forename: Alessio
authors.initials: A
authors.lastname: Giubellino
authors.forename: Fa
authors.initials: F
authors.lastname: Liu
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Lakshman
authors.initials: L
authors.lastname: Bindu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fivash
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000595:Amino Acid Sequence; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005454:Fluorescence Polarization; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D034444:Peptoids / Q000737:chemistry / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018909:src Homology Domains
chemical_list: D010455:Peptides; D034444:Peptoids; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D016650:Fluorescein-5-isothiocyanate