An endothelin-3-related synthetic biotinylated pentapeptide as a novel inhibitor of platelet-activating factor.

Abstract

Platelet-activating factor (PAF), a potent proinflammatory mediator, is involved in many inflammatory diseases. We recently reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence inhibit PAF-induced inflammation by directly binding to PAF. In this study, we investigated the effect of two synthetic biotinylated peptides, both of which have a sequence similar to Tyr-Lys-Asp-Gly-an endothelin-3 (ET-3)-related biotinylated pentapeptide (Tyr-Lys-Asp-Lys-Glu, BPET3) and a scavenger receptor CD36-related biotinylated tetrapeptide (Tyr-Lys-Gly-Lys, BPCD36)-on PAF-induced inflammation by using a rat model of hind paw oedema. BPET3 markedly inhibited PAF-induced oedema in a dose-dependent manner, and the dose that caused 50% inhibition was estimated to be approximately 2.64 nmol/paw. The inhibitory effect of BPCD36 on PAF-induced paw oedema was less than that of BPET3, while a synthetic biotinylated pentapeptide (Lys-Lys-Tyr-Asp-Glu) shuffling amino acid sequence of BPET3, an ET-1-related synthetic biotinylated pentapeptide (Leu-Met-Asp-Lys-Glu), or an ET-2-related synthetic biotinylated pentapeptide (Trp-Leu-Asp-Lys-Glu) did not inhibit PAF-induced paw oedema. Furthermore, intrinsic tryptophan fluorescence studies demonstrated that ET-3 specifically interacted with both PAF and its metabolite/precursor lyso-PAF. These results provide evidence that the Tyr-Lys-Asp region in both ET-3 and BPET3 is essential for marked inhibition of the peptide on PAF-induced inflammation, and strongly suggest that BPET3 may be useful as a novel anti-inflammatory drug targeting PAF.

• Authors: Akira Sato, Tasuku Suzuki, Kazunori Oikawa, Raiki Ohta, Keiichi Ebina
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 714 Issue 1-3 Pg. 142-7 (Aug 15 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23792041 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• CD36 Antigens
• Endothelin-3
• Oligopeptides
• Platelet Activating Factor
• 1-hexadecyl-2-acetyl-glycero-3-phosphocholine

Topics

• Amino Acid Sequence
• Animals
• Biotinylation
• CD36 Antigens (chemistry)
• Dose-Response Relationship, Drug
• Edema (chemically induced, drug therapy)
• Endothelin-3 (chemistry)
• Male
• Oligopeptides (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Platelet Activating Factor (adverse effects, analogs & derivatives, antagonists & inhibitors)
• Rats
• Rats, Wistar
• Structure-Activity Relationship