Title

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

ORCiD

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

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.