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Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis
R Binétruy-Tournaire1, C Demangel, B Malavaud
1Université Paris XIII, UFR Léonard de Vinci, UPRES 2360, 'Ciblage Fonctionnel des Tumeurs Solides', 74 rue Marcel Cachin, 93017 Bobigny Cedex, France. tournair@unice.fr
Abstract:
Vascular endothelial growth factor (VEGF) binding to the kinase domain receptor (KDR/FLK1 or VEGFR-2) mediates vascularization and tumor-induced angiogenesis. Since there is evidence that KDR plays an important role in tumor angiogenesis, we sought to identify peptides able to block the VEGF-KDR interaction. A phage epitope library was screened by affinity for membrane-expressed KDR or for an anti-VEGF neutralizing monoclonal antibody. Both strategies led to the isolation of peptides binding KDR specifically, but those isolated by KDR binding tended to display lower reactivities. Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell-displayed KDR. In vitro, this effect led to the inhibition of the VEGF-mediated proliferation of human vascular endothelial cells, in a dose-dependent and endothelial cell type-specific manner. Moreover, in vivo, ATWLPPR totally abolished VEGF-induced angiogenesis in a rabbit corneal model. Taken together, these data demonstrate that ATWLPPR is an effective antagonist of VEGF binding, and suggest that this peptide may be a potent inhibitor of tumor angiogenesis and metastasis.
Insights
A novel peptide, ATWLPPR, effectively blocks vascular endothelial growth factor (VEGF) binding to its receptor (KDR). This peptide inhibits VEGF-driven cell proliferation and angiogenesis, showing potential for cancer therapy.
Area of Science:
- Molecular Biology
- Angiogenesis Research
- Peptide Therapeutics
Background:
- Vascular endothelial growth factor (VEGF) binding to kinase domain receptor (KDR/FLK1 or VEGFR-2) is crucial for vascularization and tumor angiogenesis.
- KDR's significant role in tumor angiogenesis necessitates strategies to block VEGF-KDR interactions.
Purpose of the Study:
- To identify peptides that can effectively block the interaction between VEGF and KDR.
- To evaluate the therapeutic potential of identified peptides in inhibiting angiogenesis.
Main Methods:
- Screening of a phage epitope library for peptides binding to membrane-expressed KDR or an anti-VEGF antibody.
- Testing synthetic peptides for their ability to inhibit VEGF binding to KDR.
- In vitro assays assessing inhibition of VEGF-mediated endothelial cell proliferation.
- In vivo studies using a rabbit corneal model to evaluate inhibition of VEGF-induced angiogenesis.
Main Results:
- Peptide ATWLPPR was identified as a potent inhibitor, completely abolishing VEGF binding to cell-displayed KDR.
- ATWLPPR demonstrated dose-dependent and cell type-specific inhibition of VEGF-mediated human vascular endothelial cell proliferation in vitro.
- In vivo, ATWLPPR completely inhibited VEGF-induced angiogenesis in a rabbit corneal model.
Conclusions:
- ATWLPPR is a highly effective antagonist of VEGF binding to KDR.
- This peptide holds significant promise as a potential inhibitor of tumor angiogenesis and metastasis.