Studies on the Structure−Activity Relationship of Endostatin:  Synthesis of Human Endostatin Peptides Exhibiting Potent Antiangiogenic Activities

• Published in: Journal of medicinal chemistry Vol. 46; no. 19; pp. 4165 - 4172
• Main Authors: Chillemi, Francesco, Francescato, Pierangelo, Ragg, Enzio, Cattaneo, Maria Grazia, Pola, Sandra, Vicentini, Lucia
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 11.09.2003
• Subjects: Amino Acid Sequence; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Biological and medical sciences; Cell Division - drug effects; Cell Movement - drug effects; Cells, Cultured; Circular Dichroism; Collagen - chemical synthesis; Collagen - chemistry; Collagen - pharmacology; Endostatins; Endothelial Growth Factors - pharmacology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Endothelium, Vascular - ultrastructure; Female; Hemoglobins - analysis; Humans; Intercellular Signaling Peptides and Proteins - pharmacology; Lymphokines - pharmacology; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Endothelial cell; Peptides; Endostatin; In vitro; Vascularization; Angiogenesis; In vivo; Vascular endothelium growth factor; Structure activity relation; Peptide fragment; Polypeptide; Inhibitor; Peptide synthesis; Neovascularization; Solid phase; Antiangiogenic agent; Chemical synthesis
• DOI: 10.1021/jm0308287
• ISSN: 0022-2623

The aim of the present research was to study the relationship between chemical structure and antiangiogenic activity of endostatin. Four peptides, containing about 40 amino acid residues, designed to cover nearly the whole sequence of endostatin, were synthesized by the solid-phase method. They were termed Fragment I (sequence 6−49), II (sequence 50−92), III (sequence 93−133), and IV (sequence 134−178), with the latter bearing the original disulfide bond Cys135-Cys165. These peptides were tested for their ability to inhibit endothelial cell proliferation, migration, and both in vitro and in vivo angiogenesis assays in matrigel. Fragments I and IV inhibited cell proliferation and cell migration with a potency and an efficacy higher than that of the full length endostatin. Fragment I was also active in inhibiting in vitro the formation of tubules and in vivo the vascularization of the matrigel. Fragments II and III were devoid of antiangiogenic activity. We propose to use the peptides 6−49 and 134−178 as angiogenesis inhibitors in substitution of full length endostatin, in therapeutic applications for cancer, rheumatoid arthritis, and retinopathies.