N-叔丁氧羰基-Phe-Leu-Phe-Leu-Phe（BOC2）抑制肝素结合生长因子的血管生成活性。,Angiogenesis

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N-叔丁氧羰基-Phe-Leu-Phe-Leu-Phe（BOC2）抑制肝素结合生长因子的血管生成活性。
Angiogenesis ( IF 9.2 ) Pub Date : 2017-10-13 , DOI: 10.1007/s10456-017-9581-6
Imtiaz M Nawaz ₁ , Paola Chiodelli ₁ , Sara Rezzola ₁ , Giuseppe Paganini ₁ , Michela Corsini ₁ , Alessio Lodola ₂ , Alessio Di Ianni ₂ , Marco Mor ₂ , Marco Presta ₁

Affiliation

肽ñ -叔丁氧基羰基的Phe-LEU-PHE-LEU-PHE（BOC2）和BOC-Met的-LEU-PHE（BOC1）广泛用于甲酰肽受体（FPR中）的拮抗剂，BOC2充当FPR1 / FPR2拮抗剂，而BOC1仅抑制FPR1。通过使用这些FPR拮抗剂作为评估FPR在生理和病理状况中的作用的工具，已经进行了广泛的研究。根据我们实验室以前的观察，我们评估了BOC2可能还对血管内皮生长因子A（VEGF-A）的血管生成活性产生直接抑制作用的可能性。我们的数据表明，BOC2而不是BOC1抑制结合肝素的VEGF-A ₁₆₅的血管生成活性，而不影响结合非肝素的VEGF-A的活性₁₂₁同工型。基于内皮细胞的生物测定，表面等离子体共振分析和计算机建模表明，BOC2可能与VEGF-A ₁₆₅的肝素结合域相互作用，从而竞争肝素的相互作用并阻止VEGF-A ₁₆₅的结合酪氨酸激酶受体VEGFR2的磷酸化和下游信号转导。另外，BOC2抑制多种肝素结合血管生成生长因子与肝素的相互作用，包括其成血管活性被该化合物阻断的成纤维细胞生长因子2（FGF2）。因此，BOC2抑制了共表达VEGF-A和FGF2的人肿瘤细胞系的血管生成潜力。因此，BOC2似乎是一种新型的多肝素结合生长因子拮抗剂。这些发现对用该化合物获得的以FPR为中心的实验数据的解释提出了警告，并为设计新型BOC2衍生，独立于FPR的多靶标血管生成抑制剂奠定了基础。

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N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors.

The peptides N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) and BOC-Met-Leu-Phe (BOC1) are widely used antagonists of formyl peptide receptors (FPRs), BOC2 acting as an FPR1/FPR2 antagonist whereas BOC1 inhibits FPR1 only. Extensive investigations have been performed by using these FPR antagonists as a tool to assess the role of FPRs in physiological and pathological conditions. Based on previous observations from our laboratory, we assessed the possibility that BOC2 may exert also a direct inhibitory effect on the angiogenic activity of vascular endothelial growth factor-A (VEGF-A). Our data demonstrate that BOC2, but not BOC1, inhibits the angiogenic activity of heparin-binding VEGF-A₁₆₅ with no effect on the activity of the non-heparin-binding VEGF-A₁₂₁ isoform. Endothelial cell-based bioassays, surface plasmon resonance analysis, and computer modeling indicate that BOC2 may interact with the heparin-binding domain of VEGF-A₁₆₅, thus competing for heparin interaction and preventing the binding of VEGF-A₁₆₅ to tyrosine kinase receptor VEGFR2, its phosphorylation and downstream signaling. In addition, BOC2 inhibits the interaction of a variety of heparin-binding angiogenic growth factors with heparin, including fibroblast growth factor 2 (FGF2) whose angiogenic activity is blocked by the compound. Accordingly, BOC2 suppresses the angiogenic potential of human tumor cell lines that co-express VEGF-A and FGF2. Thus, BOC2 appears to act as a novel multi-heparin-binding growth factor antagonist. These findings caution about the interpretation of FPR-focusing experimental data obtained with this compound and set the basis for the design of novel BOC2-derived, FPR independent multi-target angiogenesis inhibitors.

更新日期：2017-10-13

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