Design and synthesis of C-terminal modified cyclic peptides as VEGFR1 antagonists

Lei Wang; Nathalie Gagey-Eilstein; Sylvain Broussy; Marie Reille-Seroussi; Florent Huguenot; Michel Vidal; Wang-Qing Liu

doi:10.3390/molecules191015391

Design and synthesis of C-terminal modified cyclic peptides as VEGFR1 antagonists

Molecules. 2014 Sep 26;19(10):15391-407. doi: 10.3390/molecules191015391.

Authors

Lei Wang¹, Nathalie Gagey-Eilstein², Sylvain Broussy³, Marie Reille-Seroussi⁴, Florent Huguenot⁵, Michel Vidal⁶, Wang-Qing Liu⁷

Affiliations

¹ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
² UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
³ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
⁴ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
⁵ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
⁶ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].
⁷ UMR 8638 CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'observatoire, Paris 75006, France. [email protected].

Abstract

Previously designed cyclic peptide antagonist c[YYDEGLEE]-NH2 disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). It represents a promising tool in the fight against cancer and age-related macular degeneration. We described in this paper the optimization of the lead peptide by C-terminal modification. A new strategy for the synthesis of cyclic peptides is developed, improving the cyclisation efficiency. At 100 µM, several new peptides with an aromatic group flexibly linked at C-terminal end showed significantly increased receptor binding affinities in competition ELISA test. The most active peptide carrying a coumarin group may be a useful tool in anti-angiogenic biological studies.

Publication types

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

MeSH terms

Amino Acid Sequence
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Binding Sites
Catalytic Domain
Drug Design*
Models, Molecular
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry*
Peptides, Cyclic / pharmacology*
Protein Binding / drug effects
Protein Conformation
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-1 / chemistry*
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factors / metabolism

Substances

Angiogenesis Inhibitors
Peptides, Cyclic
Vascular Endothelial Growth Factors
Vascular Endothelial Growth Factor Receptor-1