title: A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization.
abstract: OBJECTIVE
  Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide.
  
  
  METHODS
  Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound.
  
  
  RESULTS
  The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect.
  
  
  CONCLUSIONS
  Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Palmer
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Tiran
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Capozzi
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Coletta
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pyriochou
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kliger
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: O
authors.initials: O
authors.lastname: Levy
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: I
authors.initials: I
authors.lastname: Borukhov
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Rotman
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Penn
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USACompugen Ltd, Tel-Aviv, IsraelLaboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GreeceDepartment of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Papapetropoulos
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D042682:Angiopoietins; D010455:Peptides