Piossek Christine, Thierauch Karl-Heinz, Schneider-Mergener Jens, Volkmer-Engert Rudolf, Bachmann Martin F, Korff Thomas, Augustin Hellmut G, Germeroth Lothar
Cytos Biotechnology AG, Zurich, Switzwerland.
Thromb Haemost. 2003 Sep;90(3):501-10. doi: 10.1160/TH03-02-0106.
Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells and plays a central role in angiogenesis and vasculogenesis. Therefore, VEGF and its receptors VEGFR-1 and VEGFR-2 are prime targets for anti-angiogenic intervention which is thought to be one of the most promising approaches in cancer therapy. Recently, we have discovered a VEGFR-2-derived peptide ((247)RTELNVGIDFNWEYP(261)) representing a potential binding site to VEGF. Using the spot synthesis technique, systematic D-amino acid substitutional analyses of this peptide were conducted and the resulting D,L-peptides inhibit VEGF binding to VEGFR-2 at half maximal concentration of 30 nM. The serum-stable D,L-peptides further inhibited autophosphorylation of the VEGFR-2 at nanomolar concentrations. Testing of the peptides in a spheroid-based angiogenesis assay demonstrated a potent anti-angiogenic effect in vitro. The rational design of potent and stable anti-angiogenic peptide inhibitors from their parent receptors provides a feasible route to develop novel leads for anti-angiogenic medicines.
血管内皮生长因子（VEGF）是一种对内皮细胞有强大作用的促有丝分裂原，在血管生成和血管发生中起核心作用。因此，VEGF及其受体VEGFR-1和VEGFR-2是抗血管生成干预的主要靶点，抗血管生成干预被认为是癌症治疗中最有前景的方法之一。最近，我们发现了一种源自VEGFR-2的肽（(247)RTELNVGIDFNWEYP(261)），它代表了一个与VEGF的潜在结合位点。利用斑点合成技术，对该肽进行了系统的D-氨基酸取代分析，所得的D,L-肽在半数最大浓度为30 nM时抑制VEGF与VEGFR-2的结合。血清稳定的D,L-肽在纳摩尔浓度下进一步抑制VEGFR-2的自磷酸化。在基于球体的血管生成试验中对这些肽进行测试，结果表明其在体外具有强大的抗血管生成作用。从其母体受体合理设计强效且稳定的抗血管生成肽抑制剂，为开发抗血管生成药物的新型先导物提供了一条可行途径。
