Engineering Stabilized Vascular Endothelial Growth Factor-A Antagonists: Synthesis, Structural Characterization, and Bioactivity of Grafted Analogues of Cyclotides
Engineering Stabilized Vascular Endothelial Growth Factor-A Antagonists: Synthesis, Structural Characterization, and Bioactivity of Grafted Analogues of Cyclotides
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DOI：
10.1021/jm800704e
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Daly, Norelle L.
中科院分区：
文献类型：
--
作者：
Gunasekera, Sunithi;Foley, Fiona M.;Daly, Norelle L.
环肽类化合物是植物来源的微型蛋白质，具有紧凑的折叠结构和优异的稳定性。它们的稳定性来源于与三个保守二硫键的胱氨酸结排列偶联的头-尾环化骨架。利用这种稳定的框架，我们开发了新的VEGF-A拮抗剂，通过嫁接的肽表位参与VEGF-A拮抗到稳定的环肽框架。这类拮抗剂在血管生成是疾病进展的重要组成部分的疾病（包括癌症和类风湿性关节炎）中具有潜在的治疗应用。接枝的类似物在体外VEGF-A拮抗试验中在低微摩尔浓度下显示出生物活性，并且使用这种方法显著增加了靶表位的体外稳定性。一般来说，生物活性肽表位的稳定化是药物化学中的一个重要问题，在目前的研究中，我们提供了一种在生物环境中稳定这些肽的方法。
Cyclotides are plant derived mini-proteins with compact folded structures and exceptional stability. Their stability derives from a head-to-tail cyclized backbone coupled with a cystine knot arrangement of three-conserved disulfide bonds. Taking advantage of this stable framework we developed novel VEGF-A antagonists by grafting a peptide epitope involved in VEGF-A antagonism onto the stable cyclotide framework. Antagonists of this kind have potential therapeutic applications in diseases where angiogenesis is an important component of disease progression, including cancer and rheumatoid arthritis. A grafted analogue showed biological activity in an in vitro VEGF-A antagonism assay at low micromolar concentration and the in vitro stability of the target epitope was markedly increased using this approach. In general, the stabilization of bioactive peptide epitopes is a significant problem in medicinal chemistry and in the Current study we have provided insight into one approach to stabilize these peptides in a biological environment.