Lipopolysaccharide (LPS) detoxification of analogue peptides derived from limulus anti-LPS factor.
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.
Ren
Jiandong
J
Department of General Surgery, General Hospital of Chengdu Military Command, Chengdu 610083, China.
Gao
Hongfu
H
Tang
Min
M
Gu
Jinsong
J
Xia
Peiyuan
P
Xiao
Guangxia
G
D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D060829:Arthropod Proteins; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007422:Intestines / Q000473:pathology; D007447:Invertebrate Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D060829:Arthropod Proteins; D007447:Invertebrate Hormones; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C034705:antilipopolysaccharide factor (Limulus)