title: Synthetic biotinylated peptide compounds derived from Asp-hemolysin: novel potent inhibitors of platelet-activating factor.
abstract: Platelet-activating factor (PAF: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent inflammatory mediator, is implicated in many inflammatory diseases and may possibly serve as a direct target for anti-inflammatory drugs. We have previously reported that Asp-hemolysin-related synthetic peptides (P4-P29) inhibit the bioactivities of oxidized low-density lipoprotein (ox-LDL) containing PAF-like lipids by direct binding to ox-LDL, which plays a key role in the atherosclerotic inflammatory process. In this study, we investigated whether these peptides inhibit the bioactivities of PAF by binding to PAF and its metabolite/precursor lyso-PAF. In in vitro experiments, P21, one of the peptides, bound to both PAF and lyso-PAF in a dose-dependent manner and markedly inhibited PAF-induced apoptosis in human umbilical vein endothelial cells. Moreover, in in vivo experiments, P4 and P21, particularly their N-terminally biotinylated peptide compounds (BP4 and BP21), inhibited PAF-induced rat paw oedema dose dependently and markedly, and showed sufficient inhibition of the oedema even at doses 150-300 times less than the doses of PAF antagonists. These results provide evidence that direct binding of N-terminally biotinylated peptide compounds derived from Asp-hemolysin to PAF and lyso-PAF leads to a dramatic inhibition of the bioactivities of PAF, both in vitro and in vivo, and strongly suggesting that these compounds may be useful as a novel type of anti-inflammatory drug for the treatment of several inflammatory diseases caused by 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: Takeshi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ebina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001710:Biotin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019921:Biotinylation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy / Q000473:pathology; D005656:Fungal Proteins / Q000737:chemistry*; D006460:Hemolysin Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; C089497:Asp-HS protein, Aspergillus fumigatus; C000595069:BP21 peptide; D005656:Fungal Proteins; D006460:Hemolysin Proteins; D010446:Peptide Fragments; D010455:Peptides; D010972:Platelet Activating Factor; D001710:Biotin