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

Authors

Ricardo Jose Giordano, University of Sao Paulo, Institute of ChemistryFollow
Marina Cardo-Vila, University of New MexicoFollow
Ahmad Salameh, University of Texas Health Science Center at Houston
Cristiane D. Anobom, Federal University of Rio de JaneiroFollow
Benjamin David Zeitlin, University of the PacificFollow
David H. Hawke, University of Texas, MD Anderson Cancer CenterFollow
Ana Paula Valente, Federal University of Rio de JaneiroFollow
Fabio C. L. Almeida, Federal University of Rio de JaneiroFollow
Jacques E. Nör, University of Michigan School of DentistryFollow
Richard L. Sidman, Harvard Insitutes of MedicineFollow
Renata Pasqualini, University of New Mexico Cancer CenterFollow

ORCiD

Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188

Department

Biomedical Sciences

Document Type

Article

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

ISSN

1091-6490

Volume

107

Issue

11

DOI

10.1073/pnas.0915141107

First Page

5112

Last Page

5117

Publication Date

Winter 3-16-2010

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.

Recommended Citation

Giordano, R. J., Cardo-Vila, M., Salameh, A., Anobom, C. D., Zeitlin, B. D., Hawke, D. H., Valente, A. P., Almeida, F. C., Nör, J. E., Sidman, R. L., & Pasqualini, R. (2010). 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. DOI: 10.1073/pnas.0915141107
https://scholarlycommons.pacific.edu/dugoni-facarticles/385