title: 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.
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 VEGF165binding 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=0.18μM) 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.
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Grabowska
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Puszko
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Piotr F J
authors.initials: PF
authors.lastname: Lipiński
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Laskowska
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Wileńska
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Witkowska
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, INSERM U1125, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Gerard Y
authors.initials: GY
authors.lastname: Perret
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland; Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland. Electronic address: misicka@chem.uw.edu.pl.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Misicka
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D010456:Peptides, Cyclic; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1
keywords: A7R; Angiogenesis; Cyclic peptides; Docking analysis; NRP-1; VEGF(165)