Cyclic Limulus Anti-lipopolysaccharide (LPS) Factor-Derived Peptide CLP-19 Antagonizes LPS Function by Blocking Binding to LPS Binding Protein

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  • Liu Yao
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China
  • Ni Bing
    Department of Immunology, Third Military Medical University, China
  • Ren Jian-dong
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China Department of Pharmacy, General Hospital of Chengdu Military Command
  • Chen Jian-hong
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China
  • Tian Zhi-qiang
    Department of Immunology, Third Military Medical University, China
  • Tang Min
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China
  • Li Di
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China
  • Xia Peiyuan
    Department of Pharmacy, Southwest Hospital, Third Military Medical University, China

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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.

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