From combinatorial peptide selection to drug prototype (I): Targeting the vascular endothelial growth factor receptor pathway

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-03, Vol.107 (11), p.5112-5117
• Main Authors: Giordano, Ricardo J, Cardó-Vila, Marina, Salameh, Ahmad, Anobom, Cristiane D, Zeitlin, Benjamin D, Hawke, David H, Valente, Ana P, Almeida, Fábio C.L, Nör, Jacques E, Sidman, Richard L, Pasqualini, Renata, Arap, Wadih
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Angiogenesis; Angiogenesis inhibitors; Animals; Bacteriophages; Biological Sciences; Blood vessels; Cancer; Cells; Disease Models, Animal; Drug Design; Drug Resistance - drug effects; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - pathology; Humans; Ligands; Mice; Molecular Sequence Data; Neuropilin-1 - metabolism; Peptide Library; Peptides; Peptides - chemistry; Peptides - pharmacology; Peptides - therapeutic use; Peptidomimetics; Pharmaceuticals; Proteins; Receptors; Receptors, Vascular Endothelial Growth Factor - metabolism; Retina - drug effects; Retina - pathology; Retinal Neovascularization - drug therapy; Signal transduction; Signal Transduction - drug effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0915141107

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.