Rational design, structure, and biological evaluation of cyclic peptides mimicking the vascular endothelial growth factor.
Angiogenesis is the development of a novel vascular network from a pre-existing structure. Blocking angiogenesis is an attractive strategy to inhibit tumor growth and metastasis formation. Based on structural and mutagenesis data, we have developed novel cyclic peptides that mimic, simultaneously, two regions of the VEGF crucial for the interaction with the VEGF receptors. The peptides, displaying the best affinity for VEGF receptor 1 on a competition assay, inhibited endothelial cell transduction pathway, migration, and capillary-like tubes formation. The specificity of these peptides for VEGF receptors was demonstrated by microscopy using a fluorescent peptide derivative. The resolution of the structure of some cyclic peptides by NMR and molecular modeling has allowed the identification of various factors accounting for their inhibitory activity. Taken together, these results validate the selection of these two regions as targets to develop molecules able to disturb the development of cancer and angiogenesis-associated diseases.
Goncalves
Victor
V
Université Paris Descartes, UFR biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, 45 rue des Saints Pères, Paris, F-75006, France.
Gautier
Benoit
B
Coric
Pascale
P
Bouaziz
Serge
S
Lenoir
Christine
C
Garbay
Christiane
C
Vidal
Michel
M
Inguimbert
Nicolas
N
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D018360:Crystallography, X-Ray; D003627:Data Interpretation, Statistical; D004338:Drug Combinations; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007797:Laminin; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009154:Mutation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011509:Proteoglycans; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D005456:Fluorescent Dyes; D007797:Laminin; D010456:Peptides, Cyclic; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1