Rational design, structure, and biological evaluation of cyclic peptides mimicking the vascular endothelial growth factor

Victor Goncalves; Benoit Gautier; Pascale Coric; Serge Bouaziz; Christine Lenoir; Christiane Garbay; Michel Vidal; Nicolas Inguimbert

doi:10.1021/jm0706970

Rational design, structure, and biological evaluation of cyclic peptides mimicking the vascular endothelial growth factor

J Med Chem. 2007 Oct 18;50(21):5135-46. doi: 10.1021/jm0706970. Epub 2007 Sep 27.

Authors

Victor Goncalves¹, Benoit Gautier, Pascale Coric, Serge Bouaziz, Christine Lenoir, Christiane Garbay, Michel Vidal, Nicolas Inguimbert

Affiliation

¹ Université Paris Descartes, UFR biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, 45 rue des Saints Pères, Paris, F-75006, France.

PMID: 17900101
DOI: 10.1021/jm0706970

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemical synthesis*
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Binding Sites
Capillaries / drug effects
Capillaries / physiology
Cell Line
Cell Movement / drug effects
Collagen
Crystallography, X-Ray
Data Interpretation, Statistical
Drug Combinations
Drug Design
Endothelial Cells / drug effects
Endothelial Cells / physiology
Fluorescent Dyes / chemistry
Humans
Hydrogen Bonding
Laminin
Magnetic Resonance Spectroscopy
Microscopy, Confocal
Models, Molecular*
Molecular Mimicry
Molecular Structure
Mutation
Peptides, Cyclic / chemical synthesis*
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology
Proteoglycans
Quantitative Structure-Activity Relationship
Signal Transduction
Umbilical Veins / cytology
Vascular Endothelial Growth Factor A / chemistry*
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-1 / chemistry
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-1 / physiology*

Substances

Angiogenesis Inhibitors
Drug Combinations
Fluorescent Dyes
Laminin
Peptides, Cyclic
Proteoglycans
Vascular Endothelial Growth Factor A
matrigel
Collagen
Vascular Endothelial Growth Factor Receptor-1