Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Blood. 2011 Dec 15;118(25):6709-17. doi: 10.1182/blood-2011-06-359141. Epub 2011 Oct 28.
Fragments from the extracellular matrix proteins laminin and osteopontin and a sequence from VEGF have potent proangiogenic activity despite their small size (< 10 residues). However, these linear peptides have limited potential as drug candidates for therapeutic angiogenesis because of their poor stability. In the present study, we show that the therapeutic potential of these peptides can be significantly improved by "grafting" them into cyclic peptide scaffolds. Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1), naturally occurring, plant-derived cyclic peptides of 34 and 14 residues, respectively, were used as scaffolds in this study. Using this approach, we have designed a peptide that, in contrast to the small peptide fragments, is stable in human serum and at nanomolar concentration induces angiogenesis in vivo. This is the first report of using these scaffolds to improve the activity and stability of angiogenic peptide sequences and is a promising approach for promoting angiogenesis for therapeutic uses.
细胞外基质蛋白层粘连蛋白和骨桥蛋白的片段以及 VEGF 中的一个序列尽管大小较小（<10 个残基），但具有很强的促血管生成活性。然而，由于这些线性肽的稳定性差，它们作为治疗性血管生成的候选药物的潜力有限。在本研究中，我们表明，通过“嫁接”这些线性肽到环肽支架上，可以显著提高这些肽的治疗潜力。苦瓜胰蛋白酶抑制剂-II（MCoTI-II）和向日葵胰蛋白酶抑制剂-1（SFTI-1）分别是天然存在的、植物来源的 34 个和 14 个残基的环肽，被用作本研究中的支架。使用这种方法，我们设计了一种肽，与小肽片段相比，它在人血清中稳定，并且在纳摩尔浓度下在体内诱导血管生成。这是首次报道使用这些支架来提高血管生成肽序列的活性和稳定性的研究，这是一种很有前途的促进治疗性血管生成的方法。
