Targeting angiogenesis:: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide
Targeting angiogenesis:: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide
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DOI：
10.1073/pnas.0505047102
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发表时间：
2005-10-04
影响因子：
11.1
通讯作者：
Pedone, C
中科院分区：
文献类型：
--
作者：
D'Andrea, LD;Iaccarino, G;Pedone, C
调节血管生成是一个有吸引力的目标，因为许多病理条件依赖于新血管的生长。血管生成主要由VEGF调节，VEGF是一种对内皮细胞特异性的有丝分裂原。在过去的几年中，已经进行了许多努力来调节靶向VEGF及其受体的血管生成反应。基于VEGF与受体结合的X射线结构，我们设计了一种肽QK，其复制了VEGF结合界面的一个区域：螺旋区域17-25。QK的NMR构象分析显示其在水中采用螺旋构象，而对应于VEGF的α-螺旋区域的肽VEGF 15是非结构化的。体外和牛主动脉内皮细胞的生物学测定表明，QK结合VEGF受体，并与VEGF竞争。VEGF 15不与受体结合，表明螺旋结构是生物活性所必需的。此外，QK诱导内皮细胞增殖，激活依赖于VEGF的细胞信号传导，并增加VEGF生物学反应。QK促进毛细血管的形成和组织在体外测定基质胶。这些结果表明，VEGF的螺旋区17-25参与VEGF受体的激活。设计成类似于该区域的肽具有VEGF的许多生物学特性，因此表明该区域对于生物医学应用具有潜在的意义，并且模拟它的分子对于治疗和诊断应用可能是有吸引力的。
Modulating angiogenesis is an attractive goal because many pathological conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, we designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17-25. NMR conformation analysis of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the a-helix region of VEGF, VEGF15, is unstructured. Biological assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biological activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biological response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17-25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biological properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and molecules mimicking it could be attractive for therapeutic and diagnostic applications.