Stopping Sepsis: A Refined Approach

cb-2013-003199_0011
ACS Chem. Biol. 2013, 8, 2423

 

Lipopolysaccharides (LPS), when they interact with the Toll-like receptor-4 (TLR4)-myeloid differentiation factor 2 (MD-2) complex, lead to a signaling cascade that results in a host immune response. However, over-activation of this signaling cascade results in high levels of inflammation which often result in conditions such as sepsis syndrome. Sepsis syndrome is actually the 10th leading cause of death in the developed world, and as such it should be no surprise that attention is being given to the signaling cascade that is responsible for this condition. The logical approach is to try and block the activation of TLR4 which starts the signaling cascade. In research done by Artner et al. (ACS Chem. Biol. 2013, 8, 2423-2432) the structural characteristics of several known antagonists were explored using human and murine cell lines and the information gained was used in the development of novel synthetic antagonists.
Through the use of computational models and the existing structures of murine and human MD-2/TLR4 complexes with the antagonists Eritoran and Lipid IVa as well as the endotoxic agonist Lipid A, it was found that one of the primary reasons for the agonistic properties of Lipid A (and Lipid IVa in mice) was the flexibility of the β(1-6) linkage in the diglucosamine backbone of these molecules that allowed for a conformational change which resulted in the activation of the signaling cascade. Using this information, the authors took a new approach to solving the problem of sepsis by synthesizing new antagonists with rigid β-glucosamine (GlcN) (1-1) α-GlcN backbones that prevented the rotation that had caused Lipid IVa to be an agonist in the mouse model. This rotation is what allowed for the exposure of an acyl chain which caused the conformational changes and hydrophobicity required for interaction with the second TLR4/MD-2 LPS complex to start the signaling cascade. In creating these new agonistic molecules, the authors developed a multistep synthesis with high yield (75%) and high stereo-selectivity that even has a modular quality allowing for incorporation of different length acyl chains. This work, especially with the authors’ detailed synthetic methods, has great potential for leading to development of more effective antisepsis drugs.

Article Link: http://dx.doi.org/10.1021/cb4003199

One Reply to “Stopping Sepsis: A Refined Approach”

  1. Nice article! I wonder how late in the treatment of sepsis this treatment could be used, since decreased blood vessel accessibility could prove to be a problem.

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