title: Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor.
abstract: Blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. We describe here the structure and the biological action of a new cyclic peptide derived from vascular endothelial growth factor (VEGF). This 17-amino acid molecule designated cyclopeptidic vascular endothelial growth inhibitor (cyclo-VEGI, CBO-P11) encompasses residues 79-93 of VEGF which are involved in the interaction with VEGF receptor-2. In aqueous solution, cyclo-VEGI presents a propensity to adopt a helix conformation that was largely unexpected because only beta-sheet structures or random coil conformations have been observed for macrocyclic peptides. Cyclo-VEGI inhibits binding of iodinated VEGF165 to endothelial cells, endothelial cells proliferation, migration, and signaling induced by VEGF165. This peptide also exhibits anti-angiogenic activity in vivo on the differentiated chicken chorioallantoic membrane. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival without side effects. Taken together, these results suggest that cyclo-VEGI is an attractive candidate for the development of novel angiogenesis inhibitor molecules useful for the treatment of cancer and other angiogenesis-related diseases.
authors.affiliation: Molecular Angiogenesis Laboratory, INSERM E 0113, Université de Bordeaux 1, 33405 Talence, France.
authors.forename: Lior
authors.initials: L
authors.lastname: Zilberberg
authors.forename: Svetlana
authors.initials: S
authors.lastname: Shinkaruk
authors.forename: Olivier
authors.initials: O
authors.lastname: Lequin
authors.forename: Benoit
authors.initials: B
authors.lastname: Rousseau
authors.forename: Martin
authors.initials: M
authors.lastname: Hagedorn
authors.forename: Francesco
authors.initials: F
authors.lastname: Costa
authors.forename: Dario
authors.initials: D
authors.lastname: Caronzolo
authors.forename: Maurice
authors.initials: M
authors.lastname: Balke
authors.forename: Xavier
authors.initials: X
authors.lastname: Canron
authors.forename: Odile
authors.initials: O
authors.lastname: Convert
authors.forename: Georges
authors.initials: G
authors.lastname: Laïn
authors.forename: Karine
authors.initials: K
authors.lastname: Gionnet
authors.forename: Mario
authors.initials: M
authors.lastname: Goncalvès
authors.forename: Mireille
authors.initials: M
authors.lastname: Bayle
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bello
authors.forename: Gerard
authors.initials: G
authors.lastname: Chassaing
authors.forename: Gérard
authors.initials: G
authors.lastname: Deleris
authors.forename: Andreas
authors.initials: A
authors.lastname: Bikfalvi
mesh_terms: D000482:Allantois / Q000187:drug effects; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002196:Capillaries; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D008222:Lymphokines / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000502:physiology; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010456:Peptides, Cyclic; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C478485:cyclo-VEGI; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases