Structure-based design of a bicyclic peptide antagonist of the vascular endothelial growth factor receptors.
Dysregulated angiogenesis is implicated in several pathologies, including cancer and age-related macular degeneration. A potential antiangiogenic strategy consists in developing VEGF receptor ligands capable of preventing VEGF binding and the subsequent activation of these receptors. Herein, we describe the structure-based design of a VEGF-mimicking peptide, VG3F. This 25-mer peptide was doubly cyclized, on-resin, by formation of both a disulfide bridge and an intramolecular amide bond to constrain it to adopt a bioactive conformation. Tested on in vitro assays, VG3F was able to prevent VEGF binding to VEGF receptor 1 and inhibit both VEGF-induced signal transduction and cell migration.
Goncalves
Victor
V
Université Paris Descartes, UFR biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, Paris, France.
Gautier
Benoit
B
Garbay
Christiane
C
Vidal
Michel
M
Inguimbert
Nicolas
N
D000595:Amino Acid Sequence; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D049449:Luminescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
D010456:Peptides, Cyclic; D040262:Receptors, Vascular Endothelial Growth Factor