Synthesis of Heptose mimetics as inhibitors of bacterial enzymes or modulators of inflammation

PhD thesis defended by Jun CAO (Prof. Stéphane VINCENT) - 20/10/2022



Prof. Stéphane VINCENT, UNamur, Department of chemistry, Laboratory of bio-organic chemistry (CBO)

  • Prof. Steve LANNERS (département de chimie, UNamur), President
  • Prof. Stéphane VINCENT (département de chimie, UNamur), Secretary
  • Prof. Guillaume BERIONNI (département de chimie, UNamur)
  • Prof. Gwilherm EVANO (laboratoire de chimie organique, Université Libre de Bruxelles)
  • Dr Guido VERNIEST (Johnson & Johnson)

Since antibiotic resistance remains a major threat to public health worldwide, the development of new types of antibacterial agents provides an interesting challenge. Recently, an anti-virulence strategy emerged as an alternative strategy to develop new types of antibiotics to avoid antibiotic resistance. Lipopolysaccharide (LPS), a bacterial glycolipid, is a pivotal virulence factor of Gram-negative bacteria, whose biosynthesis pathways have received a lot of attention, in particular, the heptose biosynthesis pathway. Heptose is the first sugar that connects to Kdo2-lipid A, and are absent in mammals. The lack of heptose in the LPS structure (for instance by enzyme inhibition) leads to a strong fragilization of the bacteria. Moreover, heptose-derived metabolites HBP, H1P, and ADP-heptose have recently been identified as initiators of the ALPK1-TIFA-dependent inflammation. In this context, the inhibition of heptose biosynthesis represents a promising strategy to develop new inhibitors of enzymes involved in the heptose biosynthesis and/or new inflammation modulators.

According to these two biological applications, we propose the use of conformationally locked sugars that mimic the transition state of reactions catalyzed by glycosyl processing enzymes as inhibitors or inactivators of enzymes involved in heptose biosynthesis. This thesis started with the development of a synthetic methodology for the synthesis of sugar 1-spirocyclopropyl phosphonates. Applied to mannopyranose, this strategy allowed us to synthesize mannosyl-1-spirocyclopropyl phosphonates as new ADP-heptose analogues. Then, mannosyl spirocyclic gem-difluorocyclopropyl phosphonates were prepared through a 2+1 cyclopropanation using a glycosylidene diazirine and a difluoroalkene. This method allowed us to obtain the mannosyl spirocyclic gem-difluorocyclopropayl phosphonates and their ADP analogues. Finally, we synthesized 1-deoxy non-hydrolyzable mono/difluorinated HBP analogues as potential enzyme inhibitors and inflammation modulators. Kinetic and inhibition data of two bacterial enzymes involved in the LPS heptose biosynthesis are also provided.