Designed β-sheet peptides that inhibit proliferation and induce apoptosis in endothelial cells

• Published in: Angiogenesis (London) Vol. 4; no. 1; pp. 45 - 51
• Main Authors: MAYO, Kevin H, VAN DER SCHAFT, Daisy W. J, GRIFFIOEN, Arjan W
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 2001
• Subjects: Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides; Apoptosis - drug effects; Biological and medical sciences; Blood Proteins - chemistry; Blood vessels and receptors; Cattle; Cell Division - drug effects; Cells, Cultured; Drug Design; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Fundamental and applied biological sciences. Psychology; Humans; Interleukin-8 - chemistry; Membrane Proteins; Molecular Sequence Data; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Platelet Factor 4 - chemistry; Protein Structure, Secondary; Structure-Activity Relationship; Vertebrates: cardiovascular system; Human; Cell proliferation; Angiogenesis; Cell culture; Endothelial cell; Peptides; Physiology; Circulatory system; Apoptosis
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1023/a:1016672117477

Novel beta-sheet-forming peptide 33 mers, beta pep peptides, have been designed by using a combination approach employing basic folding principles and incorporating short sequences or proposed key residues from the beta-sheet domains of interleukin-8 (IL-8), platelet factor-4 (PF4) and bactericidal/permeability increasing protein (B/PI). Since PF4 and B/PI are anti-angiogenic and IL-8 is angiogenic, the library of 30 beta pep peptides was assayed for the ability to affect the growth of endothelial cells. Results indicate that five beta pep peptides (beta pep-2, 7, 8, 21 and 25) demonstrate greater than 50% anti-proliferative activity at 30 micrograms/ml, and one of those (beta pep-25) is similarly active at 10 micrograms/ml. Insight into the mechanism of action was probed in an apoptosis assay. Anti-proliferative activity was found to be correlated with the induction of apoptosis. For example, at 100 micrograms/ml beta pep-25 induces 85% of endothelial cells to undergo apoptosis within 2 days. These effects from beta pep peptides appear to be selective for endothelial cell (EC) because normal cells (fibroblasts and leukocytes) and various tumor cells are not significantly affected at peptide concentrations used in this study. Comparison of active and inactive beta pep sequences allows structure-function relationships to be deduced. Five hydrophobic residues and two lysines appear to be crucial to activity. This research contributes to the development of novel anti-angiogenic peptides.