Peptides derived from type I thrombospondin repeat-containing proteins of the CCN family inhibit proliferation and migration of endothelial cells.
Angiogenesis, or neovascularization, is tightly orchestrated by endogenous regulators that promote or inhibit the process. The fine-tuning of these pro- and anti-angiogenic elements (the angiogenic balance) helps establish the homeostasis in tissues, and any aberration leads to pathologic conditions. The type I thrombospondin repeats are a family of protein structural elements involved in the control of angiogenesis, and some proteins containing these repeats have been identified as negative regulators of angiogenesis. Here we identify a set of 11 novel, anti-angiogenic 18-20-amino acid peptides that are derived from proteins that belong to the CCN protein family and contain type I thrombospondin motifs. We have named these peptides spondinstatin-1, cyrostatin, connectostatin, nephroblastostatin, wispostatin-2, wispostatin-3, netrinstatin-5C, netrinstatin-5D, adamtsostatin-like-4, fibulostatin-6.1, and complestatin-C6 to reflect their origin. We have shown that these peptides inhibit proliferation and migration of human umbilical vein endothelial cells in vitro. By conducting a clustering analysis of the amino acid sequences using sequence similarity criteria and of the experimental results using a hierarchical clustering algorithm, we have demonstrated that there is an underlying correlation between the sequence and activity of the identified peptides. This combination of experimental and computational approaches introduces a novel systematic framework for studying peptide activity, identifying novel peptides with anti-angiogenic activity, and designing mimetic peptides with tailored properties.
Karagiannis
Emmanouil D
ED
Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. ekaragi1@jhmi.edu
Popel
Aleksander S
AS
D000071096:ADAMTS Proteins; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D055511:CCN Intercellular Signaling Proteins; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016000:Cluster Analysis; D003183:Complement C6 / Q000737:chemistry; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry; D007136:Immunoglobulins / Q000737:chemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D000075386:Netrin Receptors; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000737:chemistry; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D019700:Thrombospondin 1 / Q000737:chemistry*; D019699:Thrombospondins / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry
C486779:ADAMTSL4 protein, human; D020533:Angiogenesis Inhibitors; D055511:CCN Intercellular Signaling Proteins; C501848:CCN1 protein, human; C526317:CCN2 protein, human; C413323:CCN5 protein, human; C400081:CCN6 protein, human; D003183:Complement C6; D055515:Cysteine-Rich Protein 61; C488168:HMCN1 protein, human; D017874:Immediate-Early Proteins; D007136:Immunoglobulins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000075386:Netrin Receptors; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D019700:Thrombospondin 1; D019699:Thrombospondins; D014157:Transcription Factors; C115727:UNC5C protein, human; D055513:Connective Tissue Growth Factor; D000071096:ADAMTS Proteins
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