Anginex, a designed peptide that inhibits angiogenesis.
Novel beta-sheet-forming peptide 33-mers, betapep peptides, have been designed by using a combination approach employing basic folding principles and incorporating short sequences from the beta-sheet domains of anti-angiogenic proteins. One of these designed peptides (betapep-25), named anginex, was observed to be potently anti-angiogenic. Anginex specifically inhibits vascular endothelial cell proliferation and induces apoptosis in these cells, as shown by flow-cytometric detection of sub-diploid cells, TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-nick-end labelling) analysis and cell morphology. Anginex also inhibits endothelial cell adhesion to and migration on different extracellular matrix components. Inhibition of angiogenesis in vitro is demonstrated in the sprout-formation assay and in vivo in the chick embryo chorio-allantoic membrane angiogenesis assay. Comparison of active and inactive betapep sequences allows structure-function relationships to be deduced. Five hydrophobic residues and two lysines appear to be crucial to activity. This is the first report of a designed peptide having a well-defined biological function as a novel cytokine, which may be an effective anti-angiogenic agent for therapeutic use against various pathological disorders, such as neoplasia, rheumatoid arthritis, diabetic retinopathy and restenosis.
Griffioen
A W
AW
Tumor Angiogenesis Laboratory, Department of Internal Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
van der Schaft
D W
DW
Barendsz-Janson
A F
AF
Cox
A
A
Struijker Boudier
H A
HA
Hillen
H F
HF
Mayo
K H
KH
D000595:Amino Acid Sequence; D043168:Angiostatins; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D003510:Cyclohexanes; D043169:Endostatins; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides; D010958:Plasminogen / Q000494:pharmacology; D011506:Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000494:pharmacology
D003510:Cyclohexanes; D043169:Endostatins; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D012717:Sesquiterpenes; D019700:Thrombospondin 1; C111993:betapep-25 protein, synthetic; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen; D000077609:O-(Chloroacetylcarbamoyl)fumagillol