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Research Article

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, and Wadih Arap
PNAS first published February 26, 2010 https://doi.org/10.1073/pnas.0915141107
Ricardo J. Giordano
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Marina Cardó-Vila
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Ahmad Salameh
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Cristiane D. Anobom
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Benjamin D. Zeitlin
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David H. Hawke
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Ana P. Valente
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Fábio C. L. Almeida
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Jacques E. Nör
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Richard L. Sidman
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@mdanderson.org warap@mdanderson.org
Renata Pasqualini
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@mdanderson.org warap@mdanderson.org
Wadih Arap
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@mdanderson.org warap@mdanderson.org
  1. Contributed by Richard L. Sidman, January 7, 2010 (sent for review November 6, 2009)

  2. ↵ 1R.J.G. and M.C.-V. contributed equally to this work.

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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.

  • peptide
  • cancer
  • VEGFR
  • angiogenesis
  • retinopathy of prematurity

Footnotes

  • 3To whom correspondence may be addressed. E-mail: richard_sidman{at}hms.harvard.edu, rpasqual{at}mdanderson.org, or warap{at}mdanderson.org.
  • Author contributions: R.J.G., M.C.-V., A.S., C.D.A., B.D.Z., D.H.H., A.P.V., F.C.L.A., J.E.N., R.L.S., R.P., and W.A. designed research; R.J.G., M.C.-V., A.S., C.D.A., B.D.Z., and D.H.H. performed research; R.J.G., M.C.-V., A.S., C.D.A., B.D.Z., D.H.H., A.P.V., F.C.L.A., and J.E.N., contributed new reagents/analytic tools; R.J.G., M.C.-V., A.S., C.D.A., B.D.Z., D.H.H., A.P.V., F.C.L.A., J.E.N., R.L.S., R.P., and W.A. analyzed data; and R.J.G., M.C.-V., A.P.V., F.C.L.A., J.E.N., R.L.S., R.P., and W.A. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0915141107/DCSupplemental.

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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
Proceedings of the National Academy of Sciences Feb 2010, 200915141; DOI: 10.1073/pnas.0915141107

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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
Proceedings of the National Academy of Sciences Feb 2010, 200915141; DOI: 10.1073/pnas.0915141107
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