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. Issue 2 (15th January 2017)

• Record Type: Journal Article
• Authors: Grabowska, Karolina; Puszko, Anna K.; Lipiński, Piotr F.J.; Laskowska, Anna K.; Wileńska, Beata; Witkowska, Ewa; Perret, Gerard Y.; Misicka, Aleksandra
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 2(2017)
• Page Start: 597
• Page End: 602
• Publication Date: 2017-01-15
• Subjects: ABTS 2, 2′-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'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-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt -- PBS phosphate buffered saline -- SPPS solid phase peptide synthesis -- TBTU O-(benzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumtetrafluoroborate -- TFA trifluoroacetic acid -- VEGF vascular endothelial growth factor; Angiogenesis -- VEGF165 -- NRP-1 -- A7R -- Cyclic peptides -- Docking analysis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.11.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.