title: Lipopolysaccharide neutralization by a novel peptide derived from phosvitin.
abstract: Lipopolysaccharide (LPS), also known as endotoxin, is the primary trigger of sepsis, which is associated with high mortality in patients. No therapeutic agents are currently efficacious enough to protect patients from sepsis characterized by LPS-mediated tissue damage and organ failure. Previously, a phosvitin-derived peptide, Pt5, which consists of the C-terminal 55 residues of zebrafish phosvitin, has been shown to function as an antibacterial agent. In this study, we have generated six mutants by site-directed mutagenesis based on the sequence of Pt5, and found that one of the six mutants, Pt5e, showed the strongest bactericidal activities against Escherichia coli and Staphylococcus aureus. We then demonstrated that Pt5e was able to bind to LPS and lipoteichoic acid (LTA). More importantly, we showed that Pt5e significantly inhibited LPS-induced tumor-necrosis factor (TNF)-α and interleukin (IL)-1β release from murine RAW264.7 cells and considerably reduced serum TNF-α and IL-1β levels in mice. Additionally, Pt5e protected the liver from damage by LPS, and remarkably promoted the survival rate of the endotoxemia mice. Furthermore, Pt5e displayed no cytotoxicity to murine RAW264.7 macrophages and no hemolytic activity toward human red blood cells. These data together indicate that Pt5e is an endotoxin-neutralizing agent with a therapeutic potential in clinical treatment of LPS-induced sepsis.
authors.affiliation: Laboratory for Evolution & Development, Institute of Evolution & Marine Biodiversity and Department of Marine Biology, Ocean University of China, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Chen
authors.initials: C
authors.lastname: Sun
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Su
authors.forename: Shicui
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009500:Neutralization Tests; D010455:Peptides / Q000494:pharmacology*; D010774:Phosvitin / Q000737:chemistry*; D020011:Protective Agents / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013682:Teichoic Acids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010455:Peptides; D020011:Protective Agents; D011994:Recombinant Proteins; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D010774:Phosvitin
keywords: Antimicrobial peptide; Endotoxin; Lipopolysaccharide (LPS); Sepsis; Tumor necrosis factor (TNF)-α