Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain
文献类型：期刊论文
| 作者 | Long, YQ; Guo, RB; Luo, JH; Yang, DJ; Roller, PP |
| 刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
 |
| 出版日期 | 2003-10-17 |
| 卷号 | 310期号:2页码:334-340 |
| 关键词 | non-phosphorylated Grb2-SH2 antagonist thioether-bridged cyclic peptide hydrophobic residue sulfoxide linkage conformational constraint phage library global optimization chemotherapeutic agents intracellular signaling ErbB2-related cancer |
| ISSN号 | 0006-291X |
| DOI | 10.1016/j.bbrc.2003.09.022 |
| 文献子类 | Article |
| 英文摘要 | Without the presence of a phosphotyrosyl group, a phage library derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain attributed its high affinity and specificity to well-defined and highly favored interactions of its structural elements with the binding pocket of the protein. We have disclosed a significant compensatory role of the Glu(2-) sidechain for the absence of the phosphate functionality on Tyr(0) in the peptide ligand, cyclo(CH2CO-Glu(2-)Leu-Tyr(0)-Glu-Asn-Val-Gly-Met(5+)-Tyr-Cys)-amide (termed G1TE). In this study, we report the importance of hydrophobic residue at the Tyr +5 site in G1TE. Both acidic and basic amino acid substitutes arc disfavored at this position, and replacement of Met with P-tert-butyl-Ala was found to improve the antagonist properties. Besides, the polarity of the cyclization linkage was implicated as important in stabilizing the favored binding conformation. Oxidation of the thioether linkage into sulfoxide facilitated the binding to Grb2-SH2 markedly. Simultaneous modification of the three distant sites within G1TE provided the best agent with an IC50 of 220 nM, which is among the most potent non-phosphorous- and non-phosphotyrosine-mimic containing Grb2-SH2 domain inhibitors yet reported. This potent peptidomimetic provides a novel template for the development of chemotherapeutic agents for the treatment of erbB2-related cancer, Biological assays on G1TE(Gla(2-)) in which the original residue of Glu(2-) was substituted by gamma-carboxyglutamic acid (Gla) indicated that it could inhibit the interaction between activated GF receptor and Grb2 protein in cell homogenates of MDA-MB-453 breast cancer cells at the 2 muM level. More significantly, both G1TE(Gla(2-)) alone and the conjugate of GITE(Gla(2-)) with a peptide carrier can effectively inhibit intracellular association of erbB2 and Grb2 in the same cell lines with IC50 of 50 and 2 muM, respectively. (C) 2003 Elsevier Inc. All rights reserved. |
| WOS关键词 | PHOSPHATE-CONTAINING LIGANDS ; STRUCTURE-BASED DESIGN ; CANCER-CELLS ; SH3 DOMAINS ; INHIBITION ; AFFINITY ; BINDING ; REQUIREMENTS ; PROTEINS ; ADAPTER |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000185904300013 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274165]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, YQ |
| 作者单位 | 1.NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, NIH, Frederick, MD 21702 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA |
| 推荐引用方式 GB/T 7714 | Long, YQ,Guo, RB,Luo, JH,et al. Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2003,310(2):334-340. |
| APA | Long, YQ,Guo, RB,Luo, JH,Yang, DJ,&Roller, PP.(2003).Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,310(2),334-340. |
| MLA | Long, YQ,et al."Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 310.2(2003):334-340. |
入库方式： OAI收割
来源：上海药物研究所
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