title: 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.affiliation: Faculty of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai-Iino, Iwaki, Fukushima 970-8551, Japan. a-sato@iwakimu.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Tasuku
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Oikawa
authors.forename: Raiki
authors.initials: R
authors.lastname: Ohta
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ebina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D018955:CD36 Antigens / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D019334:Endothelin-3 / Q000737:chemistry*; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000009:adverse effects / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D018955:CD36 Antigens; D019334:Endothelin-3; D009842:Oligopeptides; D010972:Platelet Activating Factor; C037145:1-hexadecyl-2-acetyl-glycero-3-phosphocholine
keywords: Anti-inflammatory drug; Endothelin-3; PAF; PAF inhibitor; Platelet-activating factor; Synthetic peptide