Sweet Targets: Sugar Nucleotide Biosynthesis Inhibitors

Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors

“…We recently disclosed the first targeted sugar nucleotide probes for GMD. [9][10][11][12][13] Utilising a chemoenzymatic approach enabled synthetic pyranose modification of the GDP-sugar, [14][15][16] and delivered a C6-Me homologue 3(which was oxidised by GMD), and amide 4 as the first inhibitor (IC 50 = 112 mM). 10 Despite the value in access to such probes, molecular architectures better amenable to crossing a Gram-negative cell envelope to target the GMD active site are required.…”

Biocatalytic Approaches to Building Blocks for Enzymatic and Chemical Glycan Synthesis

“…Building on substantive earlier work to understand plant and bacterial pyrophosphorylase promiscuity, − the biocatalytic synthesis of NDP-sugars as targeted inhibitors of their relevant nonmammalian processing enzymes or as polysaccharide chain terminators is a developing area of research. − This approach is comparable to alternative chemical pyrophosphorylations, typically requiring prolonged reaction times and often resulting in low yields and complex purifications. − In this context, GlmU, a bifunctional N -acetylase and uridylyltransferase, has been used for the preparation of C6 and N -Ac-modified UDP- d -GlcNAc derivatives in good yields, but this enzyme demonstrates only limited substrate acceptance of C4-pyranose-modified substrates. ,,, Comparatively, a GDP-mannose pyrophosphorylase from Salmonella enterica displays good acceptance of C4-modified mannose-1-phosphates but a more limited acceptance for C6 modifications. − …”

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

“…A second oxidation reveals thioester 4 which, following hydrolysis, releases the product 5. As GMD does not exist in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective inhibitors to disrupt bacterial alginate production [3].…”