上海中医药大学李琦团队报道了血管内皮生长因子蛋白模拟物对血管生成的调控。相关研究成果发表在2021年12月30日出版的《美国化学会杂志》。

血管生成，即从现有的血管网络中形成新的血管，是导致肿瘤血管增殖和转移的癌细胞的标志。该过程是通过VEGF-A与VEGF受体的结合相互作用介导的。然而，配体结合后促血管生成作用和抗血管生成作用之间的平衡仍然是难以捉摸的，因此具有挑战性。

为了研究该相互作用，研究人员设计了一些基于磺酰-γ-AA肽的螺旋拟肽体，其可以有效地模拟VEGF（螺旋-α1）上的关键结合界面，用于VEGFR识别。有趣的是，尽管磺酰-γ-AA肽序列V2和V3都与VEGF受体紧密结合，但体外血管生成实验表明V3能有效抑制血管生成，而V2则能有效激活血管生成。研究结果表明，血管生成的这种独特调节可能是由于V2分别选择性结合VEGFR-1和V3选择性结合VEGFR-2的结果。因此，这些分子提供了一个转换血管生成信号的关键，其是一个平衡促血管生成因子和抗血管生成因子作用的生物学过程，其中不平衡会导致包括癌症在内的多种疾病。

此外，V2和V3在蛋白水解方面表现出显著的稳定性，表明V2和V3是干预血管生成失衡引起的疾病的有希望的治疗剂，并且也可以用作新型分子开关探针来研究VEGFR信号机制。研究结果还进一步证明了磺酰-γ-AA肽在模拟蛋白质识别和调节蛋白质-蛋白质相互作用的α-螺旋结构域方面的潜力。

附：英文原文

Title: Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor

Author: Sami Abdulkadir, Chunpu Li, Wei Jiang, Xue Zhao, Peng Sang, Lulu Wei, Yong Hu, Qi Li, Jianfeng Cai

Issue&Volume: December 30, 2021

Abstract: Angiogenesis, formation of new blood vessels from the existing vascular network, is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis. This process is mediated through the binding interaction of VEGF-A with VEGF receptors. However, the balance between pro-angiogenic and anti-angiogenic effect after ligand binding yet remains elusive and is therefore challenging to manipulate. To interrogate this interaction, herein we designed a few sulfono-γ-AA peptide based helical peptidomimetics that could effectively mimic a key binding interface on VEGF (helix-α1) for VEGFR recognition. Intriguingly, although both sulfono-γ-AA peptide sequences V2 and V3 bound to VEGF receptors tightly, in vitro angiogenesis assays demonstrated that V3 potently inhibited angiogenesis, whereas V2 activated angiogenesis effectively instead. Our findings suggested that this distinct modulation of angiogenesis might be due to the result of selective binding of V2 to VEGFR-1 and V3 to VEGFR-2, respectively. These molecules thus provide us a key to switch the angiogenic signaling, a biological process that balances the effects of pro-angiogenic and anti-angiogenic factors, where imbalances lead to several diseases including cancer. In addition, both V2 and V3 exhibited remarkable stability toward proteolytic hydrolysis, suggesting that V2 and V3 are promising therapeutic agents for the intervention of disease conditions arising due to angiogenic imbalances and could also be used as novel molecular switching probes to interrogate the mechanism of VEGFR signaling. The findings also further demonstrated the potential of sulfono-γ-AA peptides to mimic the α-helical domain for protein recognition and modulation of protein–protein interactions.

DOI: 10.1021/jacs.1c09571

Source: https://pubs.acs.org/doi/10.1021/jacs.1c09571