title: Cyclic Limulus anti-lipopolysaccharide (LPS) factor-derived peptide CLP-19 antagonizes LPS function by blocking binding to LPS binding protein.
abstract: Inflammation and septic shock due to endotoxins from Gram-negative bacteria infection continue to pose significant challenges to human healthcare. It is, therefore, necessary to develop therapeutic strategies targeting endotoxins, such as lipopolysaccharide (LPS), to prevent their potentially systemic effects. Pathogenesis due to Gram-negative bacteria involves LPS binding to the host LPS-binding protein (LBP), causing detrimental downstream signaling cascades. Our previous study showed that CLP-19, a synthetic peptide derived from the Limulus anti-LPS factor (LALF), could effectively neutralize LPS toxicity; however, the detailed mechanisms underlying this anti-LPS effect remained unexplained. Thus, we carried out investigations to determine how the CLP-19 neutralizes LPS toxicity. CLP-19 was found to block LPS binding to LBP in a dose-dependent manner, as evidenced by competitive enzyme-linked immunosorbent assay (ELISA). In peripheral blood mononuclear cells, CLP-19 blocked LPS-induced phosphorylation of mitogen activated protein kinase (MAPK) signaling proteins p38, extracellular signal-regulating kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2. Furthermore, CLP-19 potency in LPS antagonism in vitro and in vivo was directly associated with its ability to block the LPS-LBP interaction. Taken together, the results suggested that CLP-19's inhibitory effect on LPS-LBP binding and on the subsequent MAPK pathway signaling may be responsible for its anti-LPS mechanism. This peptide appears to represent a potential therapeutic agent for clinical treatment of sepsis.
authors: Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chengdu, China.
authors: Yao
authors: Y
authors: Liu
authors: Bing
authors: B
authors: Ni
authors: Jian-dong
authors: JD
authors: Ren
authors: Jian-hong
authors: JH
authors: Chen
authors: Zhi-qiang
authors: ZQ
authors: Tian
authors: Min
authors: M
authors: Tang
authors: Di
authors: D
authors: Li
authors: Peiyuan
authors: P
authors: Xia
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D060829:Arthropod Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D001181:Arthropods / Q000737:chemistry*; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D006737:Horseshoe Crabs / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000097:blood; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000382:microbiology / Q000517:prevention & control*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D060829:Arthropod Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D010456:Peptides, Cyclic; D000099231:Lipopolysaccharide-Binding Protein; C034705:antilipopolysaccharide factor (Limulus)