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

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

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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 angiogenesiswhenadministered 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 retroinversion for rapid drug discovery and development.

Original languageEnglish (US)
Pages (from-to)5112-5117
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number11
DOIs
StatePublished - Mar 16 2010
Externally publishedYes

Keywords

  • Angiogenesis
  • Cancer
  • Peptide
  • Retinopathy of prematurity
  • VEGFR

ASJC Scopus subject areas

  • General

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