Identification of Shc Src Homology 2 Domain-Binding Peptoid-Peptide Hybrids

Author:

Choi, W. J.

Kim, S. E.

Stephen, A. G.

Weidlich, I.

Giubellino, A.

Liu, F.

Worthy, K. M.

Bindu, L.

Fivash, M. J.

Nicklaus, M. C.

Bottaro, D. P.

Fisher, R. J.

Burke, T. R.
Author Address

Choi, Won Jun, Kim, Sung-Eun, Weidlich, Iwona, Liu, Fa, Nicklaus, Marc C.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Stephen, Andrew G.; Worthy, Karen M.; Bindu, Lakshman, Fisher, Robert J.] SAIC Frederick, Prot Chem Lab, Adv Technol Program, Frederick, MD 21702 USA. [Giubellino, Alessio, Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fivash, Matthew J.] NCI, Data Management Serv Inc, Frederick, MD 21702 USA.

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, K-d = 0.35 mu M). 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 mu M) (for example, for N-homoallyl analogue 50, IC50 = 6 mu M). 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 She SH2 domain-binding peptide mimetics.

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