TY - JOUR
T1 - From combinatorial peptide selection to drug prototype (I)
T2 - Targeting the vascular endothelial growth factor receptor pathway
AU - Giordano, Ricardo J.
AU - Cardó-Vila, Marina
AU - Salameh, Ahmad
AU - Anobom, Cristiane D.
AU - Zeitlin, Benjamin D.
AU - Hawke, David H.
AU - Valente, Ana P.
AU - Almeida, Fábio C.L.
AU - Nör, Jacques E.
AU - Sidman, Richard L.
AU - Pasqualini, Renata
AU - Arap, Wadih
PY - 2010/3/16
Y1 - 2010/3/16
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cancer
KW - Peptide
KW - Retinopathy of prematurity
KW - VEGFR
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U2 - 10.1073/pnas.0915141107
DO - 10.1073/pnas.0915141107
M3 - Article
C2 - 20190181
AN - SCOPUS:77950398570
SN - 0027-8424
VL - 107
SP - 5112
EP - 5117
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -