The glycero-D-mannoheptose core structure is exclusively found in bacteria, either with the 6-D configuration as in 1 or with a 6-L configuration as in ADP-heptose 3. Nucleotide-sugar 3 is the substrate of bacterial heptosyltransferases that play a key role in the biosynthesis of Lipopolysaccharide (LPS). From a medical prospective this bacterial biosynthetic pathway is important because: 1) the inhibition of the heptose processing enzymes leads to a dramatic phenotypic change that blocks the virulence of some major pathogenic gram-negative bacteria 2) It has been recently shown that heptose metabolites such as 1-3 can activate the innate immune response through a TIFA-dependent pathway.
Based on the biological relevance of the bacterial heptosides, our laboratory has synthesized different types of heptose glycomimetics illustrated in Figure 1: multivalent species based on a glycofullerene core structure 4, highly fluorinated D-heptoside 5 and heptosyltransferase inhibitor 6. Novel heptose scaffolds are now available in our laboratory and their biological evaluations will be discussed.
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