Synthetic glycolipids for exploration of inflammation/sepsis

Mammalian immune receptors trigger intracellular pro-inflammatory signaling cascades in response to infectious challenge, which promotes inflammation and contributes to recovery from infection. When bacteria leave the located area to invade the bloodstream (bacteremia), substantial amounts of bacterial Endotoxin is released into the circulation of the host resulting in the over-activation of inflammatory pathways and sepsis syndrome. The malfunction of the regulatory mechanisms during sepsis leads to the loss of control of inflammation and a life-threatening endotoxic shock (sepsis) with extraordinary high 50% mortality rate. Toll-like receptor 4 (TLR4) expressed by the host immune cells propagate the immediate immune response to Gram-negative bacterial infection and plays the central role in the initiation and progression of sepsis. Activation of TLR4 is interrelated with the activation of a newly discovered cytosolic Endotoxin receptor, caspase-4/11, which leads to programmed cell death and is deeply implicated in the development of sepsis. Activation of TLR4 contributes to the pathogenesis of numerous inflammatory, auto-immune and chronic diseases such as asthma, arthritis and cancer which highlights the significance of TLR4 as therapeutic target. Despite tremendous efforts of Pharma R&D to develop anti-sepsis drugs and immuno-modulators, no effective therapeutic remedy has been developed so far. Sepsis is increasingly reputed as the ultimate common pathway to death from infection and remains the leading cause of mortality in intensive care units. In a view of the globally expanding antibiotic resistance, the occurrence and frequency of sepsis is anticipated to rise. This will also enhance the burden of sepsis management for the healthcare economics emphasizing the importance of exploiting new approaches for treatment and prevention of sepsis as well as acute and chronic inflammation. The objective of the Grant Proposal is to develop a new class of TLR4- and caspase-4/11 specific sugar-based molecules having pronounced anti-inflammatory properties. Novel generation of innovative glycolipids will be designed, synthesised and biologically evaluated. Synthetic glycolipids based on the sugar scaffolds will block the binding of Endotoxin to respective receptor proteins (antagonist). Coordinating the immune response to infection by targeting immune receptors is a complicated process which demands precise balancing of the intracellular signaling pathways. Chemical modifications of the basic antagonist glycolipid structure will provide molecules with unique biological features - partial agonists at TLR4 and caspase-4/11. Partial agonist will compete with Endotoxin for binding on the receptor proteins, and thereby, block the induction of deleterious pro-inflammatory signaling. At the same time, exposure of TLR4 complex to partial agonist will ensure a constant, weak level of immune activation, preventing in this way the lethal sepsis-induced immunosuppression. This way of immunomodulation is a promising strategy for therapy of acute and chronic diseases ranging from autoimmune disorders to antibiotic-resistant infections. The project will be performed within tight cooperation between bioorganic chemists (Department of Chemistry, BOKU), immunologists and molecular and structural biologists (cooperation partners in Germany, Belgium, USA and China). The functional properties of synthetic glycolipids will be assessed in numerous cellular and in-vitro assays. The research project will contribute to understanding of molecular mechanisms of inflammatory diseases and will foster the invention of novel sugar-based immunotherapeutics directed to the resolution of inflammation and treatment of sepsis.