Design, SAR, Angiogenic Activities Evaluation and Pro-Angiogenic Mechanism of New Marine Cyclopeptide Analogs
Design, SAR, Angiogenic Activities Evaluation and Pro-Angiogenic Mechanism of New Marine Cyclopeptide Analogs
复制标题
新型海洋环肽类似物的设计、SAR、血管生成活性评价和促血管生成机制。
DOI：
10.2174/0929867311320090007
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发表时间：
2013-03-01
影响因子：
4.1
通讯作者：
Pang, J.
中科院分区：
文献类型：
--
作者：
Li, J.;Lu, X.;Pang, J.
血管生成在广泛的生理过程中发挥着重要作用。在本文中，我们以前期研究中能够刺激斑马鱼血管生成的海洋环肽（化合物21）为先导化合物，设计并合成了一系列新的类似物，包括11个线肽和9个环肽。在斑马鱼体内测试时，大多数合成的化合物表现出血管生成作用。其中，与先导化合物相比，化合物3、4、10和15对斑马鱼表现出更强的血管生成活性，其中线肽3和4表现出最显着的血管生成活性。 SAR（结构-活性关系）分析表明，Val、Lys 和 Ala 对该活性很重要。进一步的研究表明，3可以浓度依赖性地刺激体外HUVEC（人脐静脉内皮细胞）的增殖、迁移和侵袭。为了探究该系列化合物的血管生成机制，我们通过微阵列分析研究了基因表达谱，结果显示，3种化合物处理斑马鱼后，有26个基因上调了2倍以上，其中mmp9和mmp13a这两个血管生成相关基因上调了5倍以上。而且，通过GO（基因本体论）富集分析，mmp9和mmp13a基因是生物过程网络的中心节点。这些结果提示该类小分子肽的促血管生成机制与信号转导通路中mmp基因的表达和调控有关。此外，选择一种mmp抑制剂进行进一步确认。
Angiogenesis plays an important role in a wide range of physiological processes. In this paper, we designed and synthesized a series of new analogs including 11 line-peptides and 9 cyclo-peptides by using a marine cyclopeptide (compound 21) which could stimulate angiogenesis on zebrafish in our previous studies as lead compound. The majority of compounds synthesized exhibited angiogenic effects when tested in vivo on zebrafish. Among them, compounds 3, 4, 10, and 15 exhibited much stronger angiogenic activities on zebrafish compared with the lead compound, and the line peptides 3 and 4 showed the most significant angiogenic activities. The SAR (structure-activity relationship) analysis revealed that Val, Lys and Ala are important for the activity. Further studies showed that 3 could concentration-dependently stimulate proliferation, migration and invasion in HUVECs (human umbilical vein endothelial cells) in vitro. To explore the angiogenesis mechanism of this series of compounds, a microarray analysis was carried out to study the gene expression profile and the result showed that 26 genes were upregulated more than 2 fold changes in treatment with 3 on zebrafish, in which mmp9 and mmp13a, two angiogenesis-related genes, increased up to 5-folds. Moreover, through the GO (gene ontology) enrichment analysis, mmp9 and mmp13a genes are the central nodes in the biological processes network. These results suggested that the pro-angiogenic mechanism of this kind of small molecular peptides is related with the expression and regulation of mmp genes in the signal transduction pathways. Additionally, one mmp inhibitor was chosen for further confirmation.