Chemical synthesis of lipid A derivatives to study their immunological activities
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The lipid A moiety of lipopolysaccharides (LPS) initiates innate immune responses by interacting with Toll-like receptor 4 (TLR4), which results in the production of a wide range of cytokines. The structures of lipid As vary considerably among bacterial species, which likely accounts for the highly variable in-vivo and in-vitro host responses to LPS. To develop lipid A as immuno-modulators requires a detailed knowledge of patterns of cytokines induced by a wide range of derivatives. To achieve this end, we synthesized several lipid A derivatives by a convergent approach. The synthetic compounds and E. coli 055:B5 LPS were examined for a variety of cytokines. Significant differences in potency and efficacy were observed in the induction of cytokines by the different lipid As, which can be exploited for the development of immune-modulating therapies. All of the above synthetic lipid A derivatives have lower efficacies than E. coli 055:B5 LPS for all the tested cytokines. To exploit the specific structural features responsible for this difference, we synthesized lipid A from Neisseria meningitidis and its derivative containing 3-Deoxy-D-manno-octulosonic acid (Kdo). Examination of the biological results showed that the lipid A derivative containing Kdo was slightly less active than its parent LPS, which indicates that one Kdo moiety is sufficient for the restoration of biological activity. The lipid A from R. sin-1 can antagonize TNF-± production by human monocytes induced by E. coli LPS. To establish the relevance of its unusual long chain 27-hydroxyoctacosanoic acid for antagonistic properties, a highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. Cellular activation studies with a human monocytic cell line have shown that the octacosanoic acid is important, but not necessary for antagonistic properties. There is some indication that P. gingivalis LPS initiates innate immune responses through TLR2. To identify specific structural features that are responsible for this unusual activation pathway, we have synthesized two lipid As of P. gingivalis LPS by a highly convergent approach, which provides easy access to a wide range of lipid As.