Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1.

Abstract

Vascular endothelial growth factor receptor-1 (VEGFR-1, also known as Flt-1) is involved in complex biological processes often associated to severe pathological conditions like cancer, inflammation, and metastasis formation. Consequently, the search for antagonists of Flt-1 has recently gained a growing interest. Here we report the identification of a tetrameric tripeptide from a combinatorial peptide library built using non-natural amino acids, which binds Flt-1 and inhibits in vitro its interaction with placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) A and B (IC(50) approximately 10 microm). The peptide is stable in serum for 7 days and prevents both Flt-1 phosphorylation and the capillary-like tube formation of human primary endothelial cells stimulated by PlGF or VEGF-A. Conversely, the identified peptide does not interfere in VEGF-induced VEGFR-2 activation. In vivo, this peptide inhibits VEGF-A- and PlGF-induced neoangiogenesis in the chicken embryo chorioallantoic membrane assay. In contrast, in the cornea, where avascularity is maintained by high levels of expression of the soluble form of Flt-1 receptor (sFlt-1) that prevents the VEGF-A activity, the peptide is able to stimulate corneal mouse neovascularization in physiological condition, as reported previously for others neutralizing anti-Flt-1 molecules. This tetrameric tripeptide represents a new, promising compound for therapeutic approaches in pathologies where Flt-1 activation plays a crucial role.

• Authors: Salvatore Ponticelli, Daniela Marasco, Valeria Tarallo, Romulo J C Albuquerque, Stefania Mitola, Atsunobu Takeda, Jean-Marie Stassen, Marco Presta, Jayakrishna Ambati, Menotti Ruvo, Sandro De Falco
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 49 Pg. 34250-9 (Dec 05 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18922791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Chick Embryo
• Chorioallantoic Membrane (chemistry)
• Combinatorial Chemistry Techniques
• Cornea (metabolism)
• Gene Expression Regulation
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic
• Neovascularization, Physiologic
• Peptides (chemistry)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (chemistry, metabolism)