Puszko Anna K, Sosnowski Piotr, Hermine Olivier, Hopfgartner Gérard, Lepelletier Yves, Misicka Aleksandra
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Department of Inorganic and Analytical Chemistry, University of Geneva, 24 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland; Department of Bioanalytics, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland.
Bioorg Med Chem. 2023 Oct 30;94:117482. doi: 10.1016/j.bmc.2023.117482. Epub 2023 Sep 22.
Neuropilin-1 (NRP-1) is a major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). It may also stimulate tumour growth and metastasis independently of VEGF-A. These functions make VEGF-A/NRP-1 complex formation and its inhibition of great interest, where NRP-1 is the target for which effective ligands are sought. Design of peptide-like inhibitors represent a strategy with great potential in the treatment of NRP-1-related disorders. Here, we present the synthesis, molecular modelling, structure-activity relationship studies as well as biological evaluation of peptides with the branched sequences HN-X-Lys(hArg)-Dab-Oic-Arg-OH and HN-Lys(X-hArg)-Dab-Oic-Arg-OH. Two of the designed peptides, in which Cys was inserted in X position, expressed high affinity (∼40 nM value) for NRP-1 and were resistant to enzymatic digestion in human serum. Moreover, peptide/NRP-1 complex promoted fast intracytoplasmic protein trafficking towards the plasma membrane in breast cancer cells. Our results suggest that these compounds might be good candidates for further development of VEGF-A/NRP-1 inhibitors.
神经纤毛蛋白-1（NRP-1）是血管内皮生长因子受体-2（VEGFR-2）的主要共受体。它也可能独立于VEGF-A刺激肿瘤生长和转移。这些功能使得VEGF-A/NRP-1复合物的形成及其抑制成为备受关注的领域，其中NRP-1是寻找有效配体的靶点。设计肽类抑制剂是治疗与NRP-1相关疾病的一种极具潜力的策略。在此，我们展示了具有分支序列HN-X-Lys(hArg)-Dab-Oic-Arg-OH和HN-Lys(X-hArg)-Dab-Oic-Arg-OH的肽的合成、分子建模、构效关系研究以及生物学评估。在设计的肽中，有两种在X位置插入了半胱氨酸，对NRP-1表现出高亲和力（约40 nM值），并且在人血清中对酶消化具有抗性。此外，肽/NRP-1复合物促进了乳腺癌细胞中快速的胞质内蛋白质向质膜的转运。我们的结果表明，这些化合物可能是进一步开发VEGF-A/NRP-1抑制剂的良好候选物。
