title: Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I.
abstract: Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein in cartilage matrix that inhibits angiogenesis. It contains two distinctive structural domains: the N-terminal third of the molecule is a hydrophilic domain that contains O-linked and N-linked oligosaccharide chains, and the C-terminal two-thirds is a hydrophobic domain that contains all of the cysteine residues. In the present study, we have attempted to further uncover the structural requirements for ChM-I to exert anti-angiogenic activity by monitoring its inhibition of the vascular endothelial growth factor (VEGF)-A-induced migration of HUVEC in vitro. Site-directed mutagenesis experiments revealed that the cyclic structure formed by the disulfide bridge between Cys(83) and Cys(99) in human ChM-I is indispensable for its anti-angiogenic function. Moreover, the C-terminal hydrophobic tail (from Trp(111) to Val(120) ) was found to play an important role in ensuring the effectiveness of ChM-I activity on HUVEC. A synthetic cyclic peptide corresponding to the ChM-I region between Ile(82) to Arg(100) also inhibited the migration of HUVEC, while replacing the Cys(83) and Cys(99) residues in this peptide with Ser completely negated this inhibitory activity. An additional synthetic cyclic peptide harboring the hydrophobic C-terminal tail of ChM-I clearly mimicked the inhibitory action of this protein on the migration of HUVEC and successfully inhibited tumor angiogenesis and growth in a xenograft mouse model of human chondrosarcoma.
authors.affiliation: Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Miura
authors.forename: Jun
authors.initials: J
authors.lastname: Kondo
authors.forename: Toru
authors.initials: T
authors.lastname: Kawakami
authors.forename: Chisa
authors.initials: C
authors.lastname: Shukunami
authors.forename: Saburo
authors.initials: S
authors.lastname: Aimoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiraki
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002813:Chondrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D004220:Disulfides; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C068675:CNMD protein, human; D003545:Cysteine