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UPARANT: a urokinase receptor-derived peptide inhibitor of VEGF-driven angiogenesis with enhanced stability and in vitro and in vivo potency.

Abstract：

:This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR(88-92)) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide Ac-Arg-Glu-Arg-Phe-NH(2) (RERF) prevents both uPAR(88-92)- and VEGF-induced angiogenesis. New N-acetylated and C-amidated peptide analogues containing α-methyl α-amino acids were designed and synthesized to optimize the biochemical properties for therapeutic applications. Among these, Ac-L-Arg-Aib-L-Arg-D-Cα(Me)Phe-NH2, named UPARANT, adopts in solution a turned conformation similar to that found for RERF, is stable to sterilization in 3 mg/mL sealed vials in autoclave for 20 minutes at 120°C, is stable in blood, and displays a long-time resistance to enzymatic proteolysis. UPARANT competes with N-formyl-Met-Leu-Phe (fMLF) for binding to the formyl-peptide receptor, inhibits VEGF-directed endothelial cell migration, and prevents cytoskeletal organization and αvβ3 activation in endothelial cells exposed to VEGF. In vitro, UPARANT inhibits VEGF-dependent tube formation of endothelial cells at a 100× lower concentration than RERF. In vivo, UPARANT reduces to the basal level VEGF-dependent capillary sprouts originating from the host vessels that invaded Matrigel sponges implanted in mice, and completely prevents neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Both excellent stability and potency position UPARANT as a promising new therapeutic agent for the control of diseases fueled by excessive angiogenesis, such as cancer and inflammation.

journal_name

Mol Cancer Ther

journal_title

Molecular cancer therapeutics

authors

Carriero MV,Bifulco K,Minopoli M,Lista L,Maglio O,Mele L,Di Carluccio G,De Rosa M,Pavone V

doi

10.1158/1535-7163.MCT-13-0949

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

1092-104

issue

5

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-13-0949

journal_volume

13

pub_type

杂志文章

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