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

doi:10.1073/pnas.0915141107

New Research In

Contributed by Richard L. Sidman, January 7, 2010 (sent for review November 6, 2009)
↵ ¹R.J.G. and M.C.-V. contributed equally to this work.

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.

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.
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