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310, 378–383.
H-bond locks the side chain conformation of the pTyr-
site binding motif of 4 series and directs the malonyl
groups of Gla1 to the pTyr-binding site of Grb2-SH2
protein.
9. Shakespeare, W.; Yang, M.; Bohacek, R.; Cerasoli, F.;
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4. Conclusions
In this study, we developed a new strategy to synthesize
orthogonally protected 3-L-aminotyrosine suitable for
solid phase peptide synthesis and successfully incorpo-
rated it into a new structural motif effectively binding to
Grb2-SH2 domain with only 6-amino acids sequence.
The 3-aminotyrosine containing sulfoxide-cyclized hex-
apeptide (4b) exhibited potent Grb2-SH2 domain bind-
ing affinity with an IC50 ¼ 50 nM, which represents the
highest affinity yet reported for a hexapeptide inhibitor
against Grb2-SH2 domain free of phosphotyrosine or
phosphotyrosine mimics. The interaction between the 30-
amino group of Tyr3 and one of the carboxyl groups of
Gla1 might stabilize the favorable conformation for the
cyclic peptides binding to Grb2-SH2 domain; on the
other hand, the electron donating ability of the amino
group at the 30-position of Tyr might contribute to an
increasing interaction between the electron-rich phenyl
ring with the Arg86 and/or Arg67 side chain of the
Grb2-SH2 domain binding cavity. This fully elaborated
small peptidomimetic 4b with low-nanomolar Grb2-
SH2 domain-binding affinity and reduced peptide nature
provides a novel template for the development of
nonpTyr containing Grb2-SH2 domain antagonists, and
potentially may find value in the chemical therapeutics
of erbB2-related cancers.
12. Oligino, L.; Lung, F.-D. T.; Sastry, L.; Bigelow, J.; Cao, T.;
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Acknowledgements
21. The physicochemical data for 10: 1H NMR (CDCl3,
400 MHz): d ppm 7.8–7.3 (m, 8H), 7.2–7.0 (m, 31H), 6.71–
6.69(dd, 2H, J ¼ 1:5 Hz), 5.2 (d, 1H, J ¼ 8:4 Hz), 4.6–4.5
(m, 1H), 4.4–4.3 (m, 2H), 4.2 (t, 1H, J ¼ 6:6 Hz), 3.2–2.9
Appreciation is expressed to Prof. Xu Shen and his
colleagues of the DDDC at SIMM for the nice assis-
tance in our using Biacore 3000 instrument. This work
was supported by the funding from Chinese Academy of
Sciences (Hundred Talent Grant to Y.-Q. Long and
grant KSCX1-SW-11).
(m, 2H); EI-MS m=z (%): 416 (M-2Trt, 6), 238 (M-2Trt-
20
Fmoc, 14), 243 (Trt, 100); ½a À3 (c ¼ 1:3, DMF).
D
22. Long, Y.-Q.; Lung, T. F.-D.; Roller, P. P. Bioorg. Med.
Chem. 2003, 11, 3929–3936.
23. Peptide 4b was purified by RP-HPLC (Vydac-C18 column,
10 · 250 mm; flow rate, 2.0 mL/min), eluent A, 0.05% TFA
in H2O, eluent B, 0.05% TFA in 9:1 CH3CN–water,
gradient 20–40% B over 35 min, Rt ¼ 25.6 min; ESI-MS
(M)Hþ) 1077.20 (calcd 1077.20) (M+Naþ) 1101.5 (calcd
1101.19); Peptide 4c, gradient 20–40% B over 35 min,
Rt ¼ 28.0 min; ESI-MS (M)Hþ) 1077.2 (calcd 1077.20)
(M+Naþ) 1101.5 (calcd 1101.19).
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