Structural modification of E. Coli lipid A and KDO-lipid IVA
Foote, Matthew Ian
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Lipopolysaccharides from gram negative bacteria are responsible for signal transduction for the proinflammatory response in cells by initiating formation of TLR4/MD-2 protein complexes. Excess LPS can lead to septic shock, a condition with often fatal results. Lipid A, the inner diglucosamine region of LPS, is responsible for a majority of LPS endotoxicity. A precursor, lipid IVA, behaves as an antagonist for LPS binding. Through molecular modeling, specific alterations to the lipid A structure can be designed that may allow tuning of lipid A activity. KDO, a sialic acid derivative naturally covalently linked to lipid A in LPS, can improve endotoxic activity in lipid A. KDO was therefore covalently linked to lipid IVA to investigate its effects on lipid IVA antagonistic acitiviy. Analogues of E. coli lipid A and KDO-lipid IVA were synthesized using divergent and partially divergent synthetic schemes.