Potent inhibition of angiogenesis by D,L-peptides derived from vascular endothelial growth factor receptor 2

Christine Piossek; Karl-Heinz Thierauch; Jens Schneider-Mergener; Rudolf Volkmer-Engert; Martin F. Bachmann; Thomas Korff; Hellmut G. Augustin; Lothar Germeroth

doi:10.1160/TH03-02-0106

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(03): 501-510
DOI: 10.1160/TH03-02-0106

Vascular Development and Vessel Remodeling

Schattauer GmbH

Potent inhibition of angiogenesis by D,L-peptides derived from vascular endothelial growth factor receptor 2

Authors

Christine Piossek

¹Cytos Biotechnology AG, Zurich, Switzerland
Karl-Heinz Thierauch

²Experimental Oncology, Research Laboratories, Schering AG, Berlin, Germany
Jens Schneider-Mergener

³Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Berlin, Germany

⁴Jerini AG, Berlin, Germany
Rudolf Volkmer-Engert

³Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Berlin, Germany
Martin F. Bachmann

¹Cytos Biotechnology AG, Zurich, Switzerland
Thomas Korff

⁵Department of Vascular Biology & Angiogenesis Research, Institute of Molecular Oncology, Tumor Biology Center, Freiburg, Germany
Hellmut G. Augustin

⁵Department of Vascular Biology & Angiogenesis Research, Institute of Molecular Oncology, Tumor Biology Center, Freiburg, Germany
Lothar Germeroth

⁶IBA GmbH, Göttingen, Germany

Abstract

Summary

Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells and plays a central role in angiogenesis and vasculogenesis. Therefore, VEGF and its receptors VEGFR-1 and VEGFR-2 are prime targets for anti-angiogenic intervention which is thought to be one of the most promising approaches in cancer therapy. Recently, we have discovered a VEGFR-2-derived peptide (²⁴⁷RTELNVGIDFNWEYP²⁶¹) representing a potential binding site to VEGF. Using the spot synthesis technique, systematic D-amino acid substitutional analyses of this peptide were conducted and the resulting D, L-peptides inhibit VEGF binding to VEGFR-2 at half maximal concentration of 30 nM.The serum-stable D, L-peptides further inhibited auto-phosphorylation of the VEGFR-2 at nanomolar concentrations. Testing of the peptides in a spheroid-based angiogenesis assay demonstrated a potent anti-angiogenic effect in vitro. The rational design of potent and stable anti-angiogenic peptide inhibitors from their parent receptors provides a feasible route to develop novel leads for anti-angiogenic medicines.

Keywords

VEGFR-2 - angiogenesis - endothelial cells - spheroid sprouting assay - D - L-peptides

Full Text

References

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