From combinatorial peptide selection to drug prototype (I): Targeting the vascular endothelial growth factor receptor pathway
Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188
Proceedings of the National Academy of Sciences of the United States of America
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.
Giordano, R. J.,
Anobom, C. D.,
Zeitlin, B. D.,
Hawke, D. H.,
Valente, A. P.,
Almeida, F. C.,
Nör, J. E.,
Sidman, R. L.,
From combinatorial peptide selection to drug prototype (I): Targeting the vascular endothelial growth factor receptor pathway.
Proceedings of the National Academy of Sciences of the United States of America, 107(11), 5112–5117.