Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
Department of Medical Oncology, Cancer Institute of Medicine, Shuguang Hospital; Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
J Am Chem Soc. 2022 Jan 12;144(1):270-281. doi: 10.1021/jacs.1c09571. Epub 2021 Dec 30.
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 and bound to VEGF receptors tightly, in vitro angiogenesis assays demonstrated that potently inhibited angiogenesis, whereas activated angiogenesis effectively instead. Our findings suggested that this distinct modulation of angiogenesis might be due to the result of selective binding of to VEGFR-1 and 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 and exhibited remarkable stability toward proteolytic hydrolysis, suggesting that and 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.
血管生成，即从现有血管网络中形成新的血管，是癌细胞的一个标志，导致肿瘤血管增殖和转移。这个过程是通过 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和抗血管生成效应之间的平衡仍然难以捉摸，因此难以操纵。为了探究这种相互作用，我们设计了一些基于磺酸基-γ-AA 肽的螺旋肽模拟物，这些模拟物可以有效地模拟 VEGF（α1 螺旋）上用于 VEGFR 识别的关键结合界面。有趣的是，尽管磺酸基-γ-AA 肽序列和都与 VEGF 受体紧密结合，但体外血管生成实验表明，强烈抑制血管生成，而有效地激活血管生成。我们的研究结果表明，这种血管生成的不同调节可能是由于序列选择性结合 VEGFR-1 和 VEGFR-2 的结果。这些分子为我们提供了一个关键的方法来切换血管生成信号，这是一个平衡促血管生成和抗血管生成因子效应的生物学过程，其中失衡会导致包括癌症在内的几种疾病。此外，和对蛋白水解水解都表现出显著的稳定性，表明和是用于干预由于血管生成失衡引起的疾病状况的有前途的治疗剂，也可以用作新型分子开关探针来研究 VEGFR 信号转导的机制。这些发现还进一步证明了磺酸基-γ-AA 肽模拟α-螺旋结构域用于蛋白识别和调节蛋白-蛋白相互作用的潜力。
