Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, United States; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo 11795, Egypt.
Department of Molecular and Cellular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40536, United States.
Bioorg Chem. 2020 Jul;100:103856. doi: 10.1016/j.bioorg.2020.103856. Epub 2020 Apr 16.
The Neuropilin (Nrp) family of cell surface receptors have key physiological and pathological functions. Nrp2 is of particular interest due to its involvement in tumor metastasis. Currently, peptide and small molecule inhibitors that target Nrp utilize arginine-based molecules which have limitations due to high inherent flexibility and issues related to stability. Further, there are no known small molecule inhibitors specific for Nrp2. Recent molecular insights identify a key ligand binding region in the b1 domain of Nrp2 responsible for binding the C-terminus of its cognate ligand VEGF-C. Based on this, we report the discovery of a novel benzamidine-based inhibitor that functions through competitive inhibition of VEGF-C binding to Nrp2. Further, we have explored inhibitor functionality and selectivity by defining its structure-activity relationship (SAR) providing valuable insights on this benzamidine-based family of Nrp2 inhibitors. This study provides the basis for further development of a potent and specific small molecule inhibitor that competitively targets pathological Nrp2 function.
神经纤毛蛋白（Nrp）家族的细胞表面受体具有关键的生理和病理功能。Nrp2 特别有趣，因为它参与了肿瘤转移。目前，针对 Nrp 的肽和小分子抑制剂利用精氨酸为基础的分子，由于固有高灵活性和稳定性相关问题而存在局限性。此外，目前还没有针对 Nrp2 的已知小分子抑制剂。最近的分子研究确定了 Nrp2 b1 结构域中的一个关键配体结合区域，负责与其同源配体 VEGF-C 的 C 末端结合。基于此，我们报告了一种新型苯甲脒基抑制剂的发现，该抑制剂通过竞争性抑制 VEGF-C 与 Nrp2 的结合起作用。此外，我们通过定义其结构-活性关系 (SAR) 来探索抑制剂的功能和选择性，为基于苯甲脒的 Nrp2 抑制剂家族提供了有价值的见解。这项研究为进一步开发针对病理性 Nrp2 功能的有效和特异性小分子抑制剂奠定了基础。
