Sepsis is a potentially fatal medical emergency that can result from infection by Gram-negative bacteria in which the body's strong reaction sets off a cascade of events. Pro-inflammatory substances released when innate immune cells are activated by the sepsis pathway can result in potentially fatal tissue and organ damage. Lipopolysaccharide (LPS), which interacts with membrane proteins and LPS binding protein (LBP), is the main bacterial cause of inflammation. Recently, myeloid differentiation protein 2 (MD-2) has been identified as an attractive target of LPS antagonists and for small molecules which can fit into its hydrophobic pocket. Pro-inflammatory factor response can be inhibited by preventing LPS from interacting with MD-2. Several organic, bioactive herbal components and phytochemicals have been observed to have therapeutic effects on sepsis in the past. One such phytochemical obtained from the spice turmeric is called curcumin (Curcuma longa). Several studies have shown that curcumin can be used as powerful weapon to manage the condition of sepsis. However, its poor solubility and stability limit its activity despite its therapeutic benefits. To improve curcumin's effectiveness and lessen the aforementioned drawbacks, we altered the compound's structure by attaching carbohydrates to the aromatic moiety and adding groups to the methylene carbon. We were able to synthesize glycosylated derivatives of curcumin that show high water solubility and stability. The binding affinities of several curcumin analogs (LPS antagonists) with the membrane protein MD-2 have been determined. In this work, we demonstrate the stability and solubility of the library of curcumin analogs in addition to measuring their binding affinities using fluorescence measurements, activity using cell culture studies, and use molecular docking simulations to demonstrate the potential role of the curcumin analogs as drugs for targeting MD-2.

Investigating the role of glyco-curcumin analogs as MD-2 inhibitors in the regulation of LPS response

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