Design of a partial peptide mimetic of anginex with antiangiogenic and anticancer activity.
Based on structure-activity relationships of the angiostatic beta-sheet-forming peptide anginex, we have designed a mimetic, 6DBF7, which inhibits angiogenesis and tumor growth in mice. 6DBF7 is composed of a beta-sheet-inducing dibenzofuran (DBF)-turn mimetic and two short key amino acid sequences from anginex. This novel antiangiogenic molecule is more effective in vivo than parent anginex. In a mouse xenograft model for ovarian carcinoma, 6DBF7 is observed to reduce tumor growth by up to 80%. It is suggested that the activity is based on antiangiogenesis, because in vitro tube formation is inhibited, and because treatment of tumor-bearing mice led to a significant reduction in microvessel density within the tumor. This partial peptide mimetic is the first endothelial cell-specific molecule designed as a substitute for an angiostatic inhibitory peptide.
Mayo
Kevin H
KH
Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. mayox001@tc.umn.edu
Dings
Ruud P M
RP
Flader
Carolee
C
Nesmelova
Irina
I
Hargittai
Balasz
B
van der Schaft
Daisy W J
DW
van Eijk
Loes I
LI
Walek
Dinesha
D
Haseman
Judy
J
Hoye
Thomas R
TR
Griffioen
Arjan W
AW
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry; D002455:Cell Division; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001572:Benzofurans; D010455:Peptides; D011506:Proteins; C111993:betapep-25 protein, synthetic; C023614:dibenzofuran; D000409:Alanine