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

• DOI: 10.1073/pnas.0915141107
• Publication Date: 2010-02-27T02:34:17Z
• Authors: Ricardo J. Giordano; Marina Cardó-Vila; Ahmad Salameh; Cristiane D. Anobom; Benjamin D. Zeitlin; David H. Hawke; Ana P. Valente; Fábio C. L. Almeida; Jacques E. Nör; Richard L. Sidman; Renata Pasqualini; Wadih Arap
• Keywords: Matrigel

Inhibition of blood vessel formation is a viable therapeutic approach in angiogenesis-dependent diseases. We previously used combinatorial screening on vascular endothelial growth factor (VEGF)-activated cells to select the sequence CPQPRPLC and showed that motif Arg-Pro-Leu targets VEGF receptor-1 neuropilin-1. Here, we evaluated validated D (LPR), derivative molecule with strong antiangiogenesis attributes. This prototype drug markedly inhibits neovascularization three mouse models: Matrigel-based assay, functional human/murine formation, retinopathy prematurity. In addition its systemic activity, (LPR) also retinal angiogenesis when administered an eye-drop formulation. Finally, preliminary studies, have targeted activity experimental tumor-bearing model. These results show drugs targeting extracellular domains receptors are active, affect signal transduction, potential for clinical application. On larger context, this study illustrates power ligand-directed selection plus retro-inversion rapid discovery development.