Lipopolysaccharide (LPS) detoxification of analogue peptides derived from limulus anti-LPS factor

Peptides. 2010 Oct;31(10):1853-9. doi: 10.1016/j.peptides.2010.07.004. Epub 2010 Jul 17.

Abstract

Lipopolysaccharide (LPS) plays a critical role in the pathogenesis of sepsis due to gram-negative bacterial infections. Therefore, LPS-neutralizing molecules could have important clinical applications. Our previous work showed, CLP19, an analogue peptide derived from limulus anti-LPS factor (LALF), possessed the capacity to neutralize LPS and thereby inhibit the LPS-induced responses. However, potential cytotoxicity of CLP19 was also found, especially when added to human red blood cells. Accordingly we further developed two peptides (designated as CLP19-1 and CLP19-2) by single- and double-point amino acid substitution of CLP19, respectively, in order to reduce its toxicity and meanwhile retain the anti-LPS activity. In this study, the LPS-detoxifying effectiveness of these peptides was evaluated both in vitro and in vivo. CLP19-1 was found to dose-dependently neutralize LPS in vitro, with significantly lower hemolysis of red blood cells as compared with CLP19. Further in vivo tests verified that CLP19-1 exerted significant protective effects on mice against LPS, characterized by significantly improved survival, decreasing of tumor necrosis factor alpha (TNF-α) serum level and alleviation of tissue injury. Our work indicates that CLP19-1 is worthy of further study as potential anti-LPS agents for the management of sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / metabolism*
  • Anti-Infective Agents / pharmacology
  • Antimicrobial Cationic Peptides
  • Arthropod Proteins
  • Cell Line
  • Dose-Response Relationship, Drug
  • Endotoxemia / chemically induced
  • Endotoxemia / metabolism
  • Endotoxemia / pathology
  • Humans
  • Intestines / pathology
  • Invertebrate Hormones / genetics
  • Invertebrate Hormones / metabolism*
  • Invertebrate Hormones / pharmacology
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology
  • Liver / pathology
  • Lung / pathology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Peptides / genetics
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Survival Rate
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Arthropod Proteins
  • Invertebrate Hormones
  • Lipopolysaccharides
  • Peptides
  • Tumor Necrosis Factor-alpha
  • antilipopolysaccharide factor (Limulus)