Targeting myeloid differentiation 2 for treatment of sepsis.

Abstract

Sepsis continues to be a leading cause of intensive care unit (ICU) death. Gram-negative bacteria are among the most important pathogens of sepsis and their LPS content is regarded to be an important stimulator that elicits the systemic inflammatory reaction. MD-2 is a small secreted glycoprotein that can bind to both the hydrophobic portion of LPS and to the extracellular domain of TLR4. The interaction between MD-2 and LPS bridges the two TLR4 molecules and induces the dimerization of LPS-MD-2-TLR4, which forms the structural basis for biological functions of TLR4/MD-2 complex. Due to its essential role in mediating the interaction between LPS and TLR4, MD-2 has been extensively explored as a therapeutic target for treatment of inflammatory disorders such as sepsis. Eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site. Although eritoran showed positive results in phase I and phase II clinical trials of severe sepsis, a phase III clinical study for severe sepsis has failed. More effective therapeutic strategies are in need to treat this devastating clinical disorder.

• Authors: Guangjie Duan, Jiang Zhu, Jianhua Xu, Yousheng Liu
• Journal: Frontiers in bioscience (Landmark edition) (Front Biosci (Landmark Ed)) Vol. 19 Issue 6 Pg. 904-15 (06 01 2014) ISSN: 2768-6698 [Electronic] Singapore
• PMID: 24896325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Disaccharides
• LY96 protein, human
• Lipopolysaccharides
• Lymphocyte Antigen 96
• Sugar Phosphates
• Toll-Like Receptor 4
• eritoran

Topics

• Disaccharides (therapeutic use)
• Humans
• Lipopolysaccharides (metabolism)
• Lymphocyte Antigen 96 (antagonists & inhibitors, metabolism)
• Models, Biological
• Molecular Targeted Therapy (methods)
• Protein Binding (drug effects)
• Sepsis (drug therapy, metabolism)
• Signal Transduction (drug effects)
• Sugar Phosphates (therapeutic use)
• Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)