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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allantois / drug effects
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Amino Acid Sequence
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Angiogenesis Inhibitors / chemistry*
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Capillaries
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Cattle
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Cell Division / drug effects
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Chick Embryo
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Chorion / drug effects
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Endothelial Growth Factors / chemistry*
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Endothelial Growth Factors / pharmacology
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Endothelial Growth Factors / therapeutic use
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology*
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Glioma / blood supply
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Glioma / drug therapy
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Humans
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Intercellular Signaling Peptides and Proteins / chemistry
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Lymphokines / chemistry
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Models, Molecular
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Molecular Sequence Data
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Neovascularization, Physiologic / drug effects*
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Peptides, Cyclic / chemistry*
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Peptides, Cyclic / pharmacology
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Peptides, Cyclic / therapeutic use
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Phosphorylation
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1 / drug effects
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Vascular Endothelial Growth Factor Receptor-1 / physiology
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Vascular Endothelial Growth Factor Receptor-2 / drug effects
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Vascular Endothelial Growth Factor Receptor-2 / physiology
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Vascular Endothelial Growth Factors
Substances
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Angiogenesis Inhibitors
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Peptides, Cyclic
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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cyclo-VEGI
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases