Kukoamine B, a novel dual inhibitor of LPS and CpG DNA, is a potential candidate for sepsis treatment.
OBJECTIVE
Lipopolysaccharides (LPS) and oligodeoxynucleotides containing CpG motifs (CpG DNA) are important pathogenic molecules for the induction of sepsis, and thus are drug targets for sepsis treatment. The present drugs for treating sepsis act only against either LPS or CpG DNA. Hence, they are not particularly efficient at combating sepsis as the latter two molecules usually cooperate during sepsis. In this study, a natural alkaloid compound kukoamine B (KB) is presented as a potent dual inhibitor for both LPS and CpG DNA.


METHODS
The affinities of KB for LPS and CpG DNA were assessed using biosensor technology. Direct interaction of KB with LPS and CpG DNA were evaluated using neutralization assays. Selective inhibitory activities of KB on pro-inflammatory signal transduction and cytokine expression induced by LPS and CpG DNA were analysed by cellular assays. Protective effects of KB in a sepsis model in mice were elucidated by determining survival and circulatory LPS and tumour necrosis factor-alpha (TNF-α) concentrations.


RESULTS
KB had high affinities for LPS and CpG DNA. It neutralized LPS and CpG DNA and prevented them from interacting with mouse macrophages. KB selectively inhibited LPS- and CpG DNA-induced signal transduction and expression of pro-inflammatory mediators without interfering with signal pathways or cell viability in macrophages. KB protected mice challenged with heat-killed Escherichia coli, and reduced the circulatory levels of LPS and TNF-α.


CONCLUSIONS
This is the first report of a novel dual inhibitor of LPS and CpG DNA. KB is worthy of further investigation as a potential candidate to treat sepsis.
Medical Research Center, Southwestern Hospital, Third Military Medical University, Chongqing, China.
Xin
X
Liu
Xinchuan
X
Zheng
Ning
N
Wang
Hongwei
H
Cao
Yongling
Y
Lu
Yupeng
Y
Long
Kecen
K
Zhao
Hong
H
Zhou
Jiang
J
Zheng
D000818:Animals; D002109:Caffeic Acids / Q000378:metabolism / Q000494:pharmacology*; D018899:CpG Islands / Q000187:drug effects*; D016207:Cytokines / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D004195:Disease Models, Animal; D004926:Escherichia coli; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D051379:Mice; D018805:Sepsis / Q000188:drug therapy*; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016019:Survival Analysis
D002109:Caffeic Acids; D016207:Cytokines; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C557784:kukoamine B; D013096:Spermine