Biochemical and structural analysis of the binding determinants of a vascular endothelial growth factor receptor peptidic antagonist

Benoit Gautier; Victor Goncalves; Donatella Diana; Rossella Di Stasi; Florence Teillet; Christine Lenoir; Florent Huguenot; Christiane Garbay; Roberto Fattorusso; Luca Domenico D'Andrea; Michel Vidal; Nicolas Inguimbert

doi:10.1021/jm1002167

Biochemical and structural analysis of the binding determinants of a vascular endothelial growth factor receptor peptidic antagonist

J Med Chem. 2010 Jun 10;53(11):4428-40. doi: 10.1021/jm1002167.

Authors

Benoit Gautier¹, Victor Goncalves, Donatella Diana, Rossella Di Stasi, Florence Teillet, Christine Lenoir, Florent Huguenot, Christiane Garbay, Roberto Fattorusso, Luca Domenico D'Andrea, Michel Vidal, Nicolas Inguimbert

Affiliation

¹ Université Paris Descartes, UFR Biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, INSERM U648, 75006 Paris, France.

PMID: 20462213
DOI: 10.1021/jm1002167

Abstract

Cyclic peptide antagonist c[YYDEGLEE]-NH(2), which disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), represents a promising tool in the fight against cancer and age-related macular degeneration. Furthermore, coupled to a cyclen derivative, this ligand could be used as a medicinal imaging agent. Nevertheless, before generating such molecular probes, some preliminary studies need to be undertaken in order to define the more suitable positions for introduction of the cyclen macrocycle. Through an Ala-scan study on this peptide, we identified its binding motif, and an NMR study highlights its binding sites on the VEGFR-1D2 Ig-like domain. Guided by the structural relationship results deduced from the effect of the peptides on endothelial cells, new peptides were synthesized and grafted on beads. Used in a pull-down assay, these new peptides trap the VEGFRs, thus confirming that the identified amino acid positions are suitable for further derivatization.

Publication types

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

MeSH terms

Amino Acid Sequence
Animals
Binding Sites
Cyclams
Heterocyclic Compounds / chemistry
Humans
Luminescent Measurements
Lysine
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Imaging
Molecular Probes / chemistry
Molecular Probes / metabolism
Molecular Probes / pharmacology
Peptides, Cyclic / chemistry*
Peptides, Cyclic / metabolism*
Peptides, Cyclic / pharmacology
Phosphorylation / drug effects
Protein Binding
Protein Conformation
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
Receptors, Vascular Endothelial Growth Factor / chemistry
Receptors, Vascular Endothelial Growth Factor / metabolism*
Signal Transduction / drug effects
Structure-Activity Relationship
Substrate Specificity
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Cyclams
Heterocyclic Compounds
Molecular Probes
Peptides, Cyclic
cyclen
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Lysine