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Molecular design of functional domain-mimics of receptors and ligands

受体和配体的功能域模拟物的分子设计

基本信息

批准号：
11490029
负责人：
SUGIMURA Kazuhisa
金额：
$ 4.22万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11490029/
关键词：
Phage library Peptide mimic scFv Human antibody MCP-1 IL-6 Inhibitor Molecular design モノクロナル抗体 TNFα ペプチドミメティックス IgE IL-5

项目摘要

We tested the approach to design the peptide mimics of the receptor/ligand-binding domain by panning a phage display library using their conformational epitope-recognizing monoclonal antibodies. We demonstrated the feasibility of this approach by the reports of Nature biotechnology (16 : 267-270, 1998) and J. Immunol. (161 : 6622-6628).In this study, we attempted to design the mimic molecule of MCP-1 (monocyte chemoattractant protein-1) and IL-6. In the case of MCP-1, we successfully identified the MCP-1 peptide mimic motifs of 19 amino acids, named G25 and C27. Both motifs contain two cysteins in their sequences. The synthetic and intramolecularly disulfide-linked peptides of these motifs inhibited the chemotaxis induced by MCP-1, while their derivatives with serine in place of cysteine did not.In the case of IL-6, we identified the #37 motif which specifically bound to human IL-6. The synthetic 13 amino acid peptide of #37 motif inhibited the proliferation of human KT-3 cell lines induced with the stimulation of IL-6. On the other hand, The #37 peptide showed no inhibition on the proliferation of murine MH60 which is the IL-6-dependent cell line.Thus, the G25, C27 and #37 peptide may be the leading peptides with antagonistic activities and useful for the therapy of inflammatory and autoimmune diseases such as rheumatoid arthritis.

我们测试了通过使用其构象表位识别的单抗来平移噬菌体展示文库来设计受体/配体结合区域的多肽模拟物的方法。我们通过《自然生物技术》(16：267-270,1998)和《免疫杂志》的报告证明了这种方法的可行性。(161：6622-6628)。在本研究中，我们试图设计MCP-1(单核细胞趋化蛋白-1)和IL-6的模拟分子。以MCP-1为例，我们成功地鉴定了19个氨基酸的MCP-1模拟基序，命名为G25和C27。这两个基序都含有两个半胱氨酸。这些基序的人工合成的和分子内二硫键连接的多肽抑制MCP-1诱导的趋化作用，而它们的衍生物用丝氨酸代替半胱氨酸不能抑制MCP-1诱导的趋化作用。人工合成的37个基序的13个氨基酸多肽抑制IL-6刺激的人KT-3细胞株的增殖。另一方面，#37肽对依赖IL-6的小鼠MH60细胞的增殖无抑制作用，因此，G25、C27和#37肽可能是具有拮抗活性的主要多肽，可用于类风湿关节炎等炎症性和自身免疫性疾病的治疗。