Synthesis of Heptose Mono- and Bisphosphate Analogues as Modulators of the Bacterial Innate Immunity and Inhibitors of the Bacterial Lipopolysaccharide

Promoter

Prof. Stéphane Vincent, UNamur, Laboratory of Bio-Organic Chemistry (CBO)

Jury

Johan WOUTERS (UNamur), President; Stéphane VINCENT (UNamur), Supervisor and Secretary; Christophe BIOT (Université de Lille); Steven BALLET (Vrije Universiteit Brussel); Steve LANNERS (UNamur).

Summary

The inhibition of the bacterial heptose biosynthesis represents a promising strategy for the development of antivirluence agents. D-glycero-D-manno-heptose 1β,7-bisphosphate (HBP) and D-glycero-D-manno-heptose 1-phosphate (H1P) are two substrates in the heptose biosynthesis. Interestingly, HBP was recently found to induce a TIFA-dependent inflammation, which was absolutely unprecedented for such bacterial metabolites. Based on these two biological questions, this PhD thesis mainly focused on the synthesis of natural products HBP and H1P, as well as their phosphonate analogues. Finally, in order to identify the natural receptor of HBP in human cells, a biotinylated probe was designed and synthesized. All these analogues have been tested on inflammatory cells. The results showed that three analogues could induce a TIFA-dependent inflammatory response, and two analogues could antagonize the inflammatory response induced by HBP. In addition, the inhibition study of the bacterial heptose biosynthesis is ongoing.