Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1.
Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1.
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通过拮抗血管内皮生长因子受体 1 的四聚体三肽调节血管生成。
DOI：
10.1074/jbc.m806607200
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
DeFalco,Sandro
中科院分区：
文献类型：
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作者：
Ponticelli,Salvatore;Marasco,Daniela;Tarallo,Valeria;Albuquerque,RomuloJC;Mitola,Stefania;Takeda,Atsunobu;Stassen,Jean-Marie;Presta,Marco;Ambati,Jayakrishna;Ruvo,Menotti;DeFalco,Sandro
血管内皮生长因子受体-1(VEGFR-1，又称Flt-1)参与复杂的生物学过程，通常与癌症、炎症和转移形成等严重的病理条件有关。因此，寻找Flt-1的拮抗剂最近引起了越来越大的兴趣。在这里，我们报道了从使用非天然氨基酸构建的组合肽文库中鉴定出一个四聚体三肽，该组合肽库结合Flt-1和抑制蛋白与胎盘生长因子和血管内皮生长因子A和B(IC50∼10；m)的相互作用。该多肽在血清中稳定7天，可阻止Flt-1的磷酸化和PlGF或VEGF-A刺激的人原代内皮细胞毛细血管样管的形成。相反，所鉴定的多肽不干扰血管内皮生长因子受体-2的激活。在体内，该多肽在鸡胚绒毛尿囊膜实验中抑制血管内皮生长因子-A和PlGF诱导的新生血管生成。相比之下，在角膜中，通过高水平表达可溶性形式的Flt-1受体(sFlt-1)来维持无血管功能，阻止了VEGF-A的活性，这种多肽能够在生理条件下刺激角膜小鼠新生血管，就像之前报道的其他中和抗Flt-1分子的小鼠一样。这种四聚体三肽代表了一种新的，有希望的化合物，用于病理中Flt-1激活发挥关键作用的治疗方法。
Vascular endothelial growth factor receptor-1 (VEGFR-1, also known as Flt-1) is involved in complex biological processes often associated to severe pathological conditions like cancer, inflammation, and metastasis formation. Consequently, the search for antagonists of Flt-1 has recently gained a growing interest. Here we report the identification of a tetrameric tripeptide from a combinatorial peptide library built using non-natural amino acids, which binds Flt-1 and inhibitsin vitroits interaction with placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) A and B (IC50∼ 10 ;m). The peptide is stable in serum for 7 days and prevents both Flt-1 phosphorylation and the capillary-like tube formation of human primary endothelial cells stimulated by PlGF or VEGF-A. Conversely, the identified peptide does not interfere in VEGF-induced VEGFR-2 activation.In vivo, this peptide inhibits VEGF-A- and PlGF-induced neoangiogenesis in the chicken embryo chorioallantoic membrane assay. In contrast, in the cornea, where avascularity is maintained by high levels of expression of the soluble form of Flt-1 receptor (sFlt-1) that prevents the VEGF-A activity, the peptide is able to stimulate corneal mouse neovascularization in physiological condition, as reported previously for others neutralizing anti-Flt-1 molecules. This tetrameric tripeptide represents a new, promising compound for therapeutic approaches in pathologies where Flt-1 activation plays a crucial role.