Global optimization of conformational constraint on non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain
文献类型：期刊论文
| 作者 | Long, YQ; Lung, FDT; Roller, PP |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2003-09-01 |
| 卷号 | 11期号:18页码:3929-3936 |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/S0968-0896(03)00411-5 |
| 文献子类 | Article |
| 英文摘要 | Following our earlier work on a phage library derived non-phosphorylated thioether-cyclized peptide inhibitor of Grb2 SH2 domain, a series of small peptide analogues with various cyclization linkage or various ring size were designed and synthesized and evaluated to investigate the optimal conformational constraint for this novel Grb2-SH2 blocker. Our previous SAR studies have indicated that constrained conformation as well as all amino acids except Leu(2) and Gly(7) in this lead peptide, cyclo(CH2CO-Glu(1)-Leu-Tyr-Glu-Asn-Val-Gly-Met-Tyr-Cys(10))-amide (termed GITE), was necessary for sustenance of the biological activity. In this study, in an effort to derive potent and bioavailable Grb2-SH2 inhibitor with minimal sequence, we undertook a systematic conformational study on this non-phosphorylated cyclic ligand by optimizing the ring linkage, ring configuration and ring size. The polarity and configuration of the cyclization linkage were implicated important in assuming the active conformation. Changing the flexible thioether linkage in G1TE into the relatively rigid sulfoxide linkage secured a 4-fold increase in potency (4, IC50= 6.5 muM). However, open chain, shortening or expanding the ring size led to a marked loss of inhibitory activity. Significantly, the introduction of omega-amino carboxylic acid linker in place of three C-terminal amino acids in G1TE can remarkably recover the apparently favorable conformation, which is otherwise lost because of the reduced ring size. This modification, combined with favorable substitutions of Gla for Glu(1) and Adi for Glu(4) in the resulting six-residue cyclic peptide, afforded peptide 19, with an almost equal potency (19, IC50 = 23.3 muM) relative to G1TE. Moreover, the lipophilic chain in omega-amino carboxylic acid may confer better cell membrane permeability to 19. These newly developed G1TE analogues with smaller ring size and less peptide character but equal potency can serve as templates to derive potent and specific non-phosphorylated Grb2-SH2 antagonists. (C) 2003 Elsevier Ltd. All rights reserved. |
| WOS关键词 | SH2 DOMAIN ; ADAPTER PROTEIN ; HIGH-AFFINITY ; BINDING ; INHIBITORS ; RECEPTOR ; PHOSPHOTYROSINE ; REQUIREMENTS ; CANCER |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000185037900009 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274192]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Long, YQ |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China 2.NCI, Med Chem Lab, Div Basic Sci, NIH,FCRDC, Frederick, MD 21702 USA |
| 推荐引用方式 GB/T 7714 | Long, YQ,Lung, FDT,Roller, PP. Global optimization of conformational constraint on non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2003,11(18):3929-3936. |
| APA | Long, YQ,Lung, FDT,&Roller, PP.(2003).Global optimization of conformational constraint on non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain.BIOORGANIC & MEDICINAL CHEMISTRY,11(18),3929-3936. |
| MLA | Long, YQ,et al."Global optimization of conformational constraint on non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain".BIOORGANIC & MEDICINAL CHEMISTRY 11.18(2003):3929-3936. |
入库方式： OAI收割
来源：上海药物研究所
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