Structure-activity relationship study of a small cyclic peptide H-c[Lys-Pro-Glu]-Arg-OH: a potent inhibitor of Vascular Endothelial Growth Factor interaction with Neuropilin-1

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• 作者：Karolina Grabowska^a ; Anna K. Puszko^a ; Piotr F.J. Lipiński^b ; Anna K. Laskowska^b ; Beata Wileńska^a ; Ewa Witkowska^a ; Gerard Y. Perret^c ; Aleksandra Misicka^a ; ^b ; ^{misicka@chem.uw.edu.pl}
• 关键词：ABTS ; 2 ; 2&prime ; -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt ; ACN ; acetonitrile ; BSA ; bovine serum albumin ; (bt)-VEGF165 ; biotinylated-VEGF165 ; 6-Cl-HOBt ; 6-chloro-1-hydroxybenzotriazole dihydrate ; DIPEA ; N ; N-diisopropylethylamine ; DMEM ; Dulbecco&rsquo ; s Modified Eagle Medium ; EGM ; Endothelial Cell Growth Media ; ELISA ; enzyme-linked immunosorbent assay ; FA ; formic acid ; MDA-MB-231 ; human breast adenocarcinoma cells ; MTS ; 3-(4 ; 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxypheny
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：597-602
• 全文大小：1009 K
• 卷排序：25

文摘

Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50 = 0.18 μM) in our previous study. We report the design, synthesis, in vitro assays and docking analysis of four small cyclic peptides (14-,15-membered ring) and one bigger cyclic compound (30-membered ring). Our study shows that both the ring size and configuration of amino acid residues present in the structure are crucial for high inhibitory effect.