Biotinylated heptapeptides substituted with a D-amino acid as platelet-activating factor inhibitors.

Abstract

Platelet-activating factor (PAF), a potent lipid mediator, is implicated in many inflammatory diseases, and therefore may serve as a direct target for anti-inflammatory drugs. We previously reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence markedly inhibit PAF-induced inflammation by direct binding, and that two synthetic fluorescence-labelled heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp and D-Lys-Trp-Tyr-Lys-Asp-Gly-Asp) with high stability in plasma specifically bind to PAF-like lipids (oxidized- and lyso-phosphatidylchoine). In this study, synthetic heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp) coupled to a biotin molecule through the N-terminal amino group and ε-amino group of N-terminus Lys, (Btn)KP6 and K(Btn)P6, respectively, and their biotinylated peptides substituted with D-Lys at the N-terminus, (Btn)dKP6 and dK(Btn)P6, respectively, were investigated for their effects on PAF-induced inflammation. In the experiments using a rat model of hind paw oedema, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 significantly inhibited PAF-induced paw oedema, with the highest inhibitory effect exhibited by dK(Btn)P6. The inhibitory effect of D-Tyr-D-Lys-D-Asp-Gly tetrapeptide on PAF-induced paw oedema was much lower than that of Tyr-Lys-Asp-Gly tetrapeptide. In the experiments using tryptophan fluorescence spectroscopy, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 bound to PAF dose-dependently, with dK(Btn)P6 showing the strongest binding affinity, indicating that its affinity appears to be closely correlated with its inhibitory effect on PAF-induced inflammation. These results suggest that direct binding of (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 to PAF can lead to marked inhibition of PAF-induced inflammation, and these agents, particularly dK(Btn)P6, may be useful as anti-inflammatory drugs targeting PAF with high stability in plasma.

• Authors: Akira Sato, Izumi Yokoyama, Keiichi Ebina
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 764 Pg. 202-207 (Oct 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26142829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids
• Anti-Inflammatory Agents
• Oligopeptides
• Platelet Activating Factor

Topics

• Amino Acids (chemistry)
• Animals
• Anti-Inflammatory Agents (chemistry, therapeutic use)
• Biotinylation
• Edema (chemically induced, drug therapy)
• Male
• Oligopeptides (chemistry, therapeutic use)
• Platelet Activating Factor (antagonists & inhibitors)
• Rats, Wistar