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Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-03 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00047 Paramjit S. Bansal 1 , Michael J. Smout 1 , David Wilson 1 , Claudia Cobos Caceres 1 , Mohadeseh Dastpeyman 1 , Javier Sotillo 1 , Julia Seifert 1 , Paul J. Brindley 2 , Alex Loukas 1 , Norelle L. Daly 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-03 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00047 Paramjit S. Bansal 1 , Michael J. Smout 1 , David Wilson 1 , Claudia Cobos Caceres 1 , Mohadeseh Dastpeyman 1 , Javier Sotillo 1 , Julia Seifert 1 , Paul J. Brindley 2 , Alex Loukas 1 , Norelle L. Daly 1
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Granulins are a family of protein growth factors that are involved in cell proliferation. An orthologue of granulin from the human parasitic liver fluke Opisthorchis viverrini, known as Ov-GRN-1, induces angiogenesis and accelerates wound repair. Recombinant Ov-GRN-1 production is complex and poses an obstacle for clinical development. To identify the bioactive region(s) of Ov-GRN-1, four truncated N-terminal analogues were synthesized and characterized structurally using NMR spectroscopy. Peptides that contained only two native disulfide bonds lack the characteristic granulin β-hairpin structure. Remarkably, the introduction of a non-native disulfide bond was critical for formation of β-hairpin structure. Despite this structural difference, both two and three disulfide-bonded peptides drove proliferation of a human cholangiocyte cell line and demonstrated potent wound healing in mice. Peptides derived from Ov-GRN-1 are leads for novel wound healing therapeutics, as they are likely less immunogenic than the full-length protein and more convenient to produce.
中文翻译：
基于Fluke Granulin结构折叠的强效伤口愈合剂的开发
颗粒蛋白是涉及细胞增殖的蛋白质生长因子家族。来自人寄生性肝吸虫Opisthorchis viverrini的颗粒蛋白直向同源物，称为Ov -GRN-1，可诱导血管生成并加速伤口修复。重组Ov -GRN-1的生产很复杂，并且对临床发展构成了障碍。识别卵的生物活性区域-GRN-1，合成了四个截短的N末端类似物，并使用NMR光谱进行了结构表征。仅包含两个天然二硫键的肽缺乏特征性的颗粒蛋白β-发夹结构。值得注意的是，引入非天然二硫键对于β-发夹结构的形成至关重要。尽管存在这种结构差异，但是两个和三个二硫键结合的肽都可以驱动人胆管细胞细胞系的增殖，并在小鼠中显示出强大的伤口愈合能力。衍生自Ov -GRN-1的肽是新型伤口愈合疗法的先导，因为它们的免疫原性可能低于全长蛋白，并且更易于生产。
更新日期：2017-05-03
中文翻译：
基于Fluke Granulin结构折叠的强效伤口愈合剂的开发
颗粒蛋白是涉及细胞增殖的蛋白质生长因子家族。来自人寄生性肝吸虫Opisthorchis viverrini的颗粒蛋白直向同源物，称为Ov -GRN-1，可诱导血管生成并加速伤口修复。重组Ov -GRN-1的生产很复杂，并且对临床发展构成了障碍。识别卵的生物活性区域-GRN-1，合成了四个截短的N末端类似物，并使用NMR光谱进行了结构表征。仅包含两个天然二硫键的肽缺乏特征性的颗粒蛋白β-发夹结构。值得注意的是，引入非天然二硫键对于β-发夹结构的形成至关重要。尽管存在这种结构差异，但是两个和三个二硫键结合的肽都可以驱动人胆管细胞细胞系的增殖，并在小鼠中显示出强大的伤口愈合能力。衍生自Ov -GRN-1的肽是新型伤口愈合疗法的先导，因为它们的免疫原性可能低于全长蛋白，并且更易于生产。
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