Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Molecules. 2019 May 6;24(9):1756. doi: 10.3390/molecules24091756.
Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2% to 58.1% at 10 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, , IC = 8.39 μM). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound and discuss the observed structure-activity relationships.
抑制神经纤毛蛋白-1（NRP-1）与血管内皮生长因子（VEGF）的相互作用已成为潜在抗癌疗法的一个有趣机制。在我们之前的工作中，我们已经获得了几种这种相互作用的亚毫摩尔抑制剂，包括具有一般结构 Lys(Har)-Xxx-Xxx-Arg 的支化五肽。为了提高我们抑制剂的蛋白水解稳定性，我们将注意力转向 1,4-二取代 1,2,3-三唑作为肽键等排体。在本研究中，我们报告了 23 种新型三唑肽及其抑制活性。这些化合物是使用典型的肽化学方法合成的，但完全在固体载体上将胺转化为叠氮化物。合成衍生物的抑制活性在 10 μM 浓度下从 9.2%到 58.1%不等（最佳化合物 Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg，IC = 8.39 μM）。合成的肽三唑在人血浆中的稳定性进行了测试，显示出对蛋白水解的显著抗性，半衰期远远超过 48 小时。体外细胞存活试验对骨髓来源的小鼠细胞 32D 的活力没有显著影响。通过分子动力学，我们能够提出化合物的结合模式，并讨论观察到的结构-活性关系。
