Structural studies of the binding of an antagonistic cyclic peptide to the VEGFR1 domain 2.

Abstract

Physiological and pathological angiogenesis is mainly regulated by the binding of the vascular endothelial growth factor (VEGF) to its receptors (VEGFRs). Antagonists of VEGFR are very attractive for the treatment of diseases related to excessive angiogenesis. Our previously designed C-terminal alkylated cyclic peptides [YKDEGLEE]-NHR (R = alkyl, arylalkyl) disrupt the interaction between VEGF and VEGFRs in biological assays. In this paper, we described the structural studies of the binding of one of these cyclic peptides named Peptide 3 to the VEGFR1 domain 2 (VEGFR1-D2). The molecular docking and NMR mapping identified the binding site on VEGFR1-D2. The anti-angiogenic effect of our peptide was evaluated by an experiment of VEGF-induced tube formation in two cell lines, retinal cell type RF6/A and vascular endothelial cell type HUVEC. Some new peptides were also synthesized and compared by an ELISA-based assay, in order to verify their ability to disrupt the formation of the complex VEGF-A/VEGFR1. In conclusion, the structural studies of Peptide 3 with VEGFR1-D2 will help the design of more efficient VEGFR antagonists. Moreover, Peptide 3, with improved receptor binding affinity, could be more suitable for VEGFR targeting bioimaging studies once labeled.

• Authors: Lei Wang, Pascale Coric, Sylvain Broussy, Rossella Di Stasi, Lingyu Zhou, Luca D D'Andrea, Lili Ji, Michel Vidal, Serge Bouaziz, Wang-Qing Liu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 169 Pg. 65-75 (May 01 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30856407 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Peptides, Cyclic
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Binding Sites (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Haplorhini
• Humans
• Molecular Structure
• Peptides, Cyclic (chemistry, pharmacology)
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, metabolism)