title: From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway.
abstract: Inhibition of blood vessel formation is a viable therapeutic approach in angiogenesis-dependent diseases. We previously used a combinatorial screening on vascular endothelial growth factor (VEGF)-activated endothelial cells to select the sequence CPQPRPLC and showed that the motif Arg-Pro-Leu targets VEGF receptor-1 and neuropilin-1. Here, we evaluated and validated (D)(LPR), a derivative molecule with strong antiangiogenesis attributes. This prototype drug markedly inhibits neovascularization in three mouse models: Matrigel-based assay, functional human/murine blood vessel formation, and retinopathy of prematurity. In addition to its systemic activity, (D)(LPR) also inhibits retinal angiogenesis when administered in an eye-drop formulation. Finally, in preliminary studies, we have showed targeted drug activity in an experimental tumor-bearing mouse model. These results show that drugs targeting extracellular domains of VEGF receptors are active, affect signal transduction, and have potential for clinical application. On a larger context, this study illustrates the power of ligand-directed selection plus retro-inversion for rapid drug discovery and development.
authors.affiliation: David H Koch Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Giordano
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salameh
authors.forename: Cristiane D
authors.initials: CD
authors.lastname: Anobom
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Zeitlin
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.forename: Ana P
authors.initials: AP
authors.lastname: Valente
authors.forename: Fábio C L
authors.initials: FC
authors.lastname: Almeida
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D039942:Neuropilin-1 / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D054852:Small Molecule Libraries; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor