Beta-sheet is the bioactive conformation of the anti-angiogenic anginex peptide.
Anginex is a designed peptide 33mer that functions as a cytokine-like agent to inhibit angiogenesis. Although this short linear peptide has been shown by NMR and CD to form a nascent beta-sheet conformation in solution, the actual bioactive structure formed upon binding to its receptor on the surface of endothelial cells could be quite different. By using a series of double-cysteine disulphide-bridged analogues, we provide evidence in the present study that the beta-sheet is in fact the bioactive conformation of anginex. CD and NMR spectral analysis of the analogues indicate formation of a beta-sheet conformation. Three functional assays, endothelial cell proliferation, apoptosis and in vitro angiogenesis, were performed on all analogues. As long as the placement of disulphide bonds preserved the beta-strand alignment, as in the proposed bioactive conformation, bioactivities were preserved. Knowledge of the bioactive conformation of anginex will aid in the design of smaller molecule mimetics of this potent anti-angiogenic peptide.
Dings
Ruud P M
RP
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Health Science Center, 6-155 Jackson Hall, 321 Church Street, Minneapolis, MN 55455, USA.
Arroyo
Monica M
MM
Lockwood
Nathan A
NA
van Eijk
Loes I
LI
Haseman
Judy R
JR
Griffioen
Arjan W
AW
Mayo
Kevin H
KH
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D010455:Peptides; D011506:Proteins; C111993:betapep-25 protein, synthetic