Synthetic UDP-Furanoses as Potent Inhibitors of Mycobacterial Galactan Biogenesis

Abstract

SUMMARY UDP-galactofuranose (UDP-Galf) is a substrate for two types of enzymes, UDP-galactopyranose mutase and galactofuranosyltransferases, which are present in many pathogenic organisms but absent from mammals. In particular, these enzymes are involved in the biosynthesis of cell wall galactan, a polymer essential for the survival of the causative agent of tuberculosis, Mycobacterium tuberculosis. We describe here the synthesis of derivatives of UDP-Galf modified at C-5 and C-6 using a chemoenzymatic route. In cell-free assays, these compounds prevented the formation of mycobacterial galactan, via the production of short “dead-end” intermediates resulting from their incorporation into the growing oligosaccharide chain. Modified UDP-furanoses thus constitute novel probes for the study of the two classes of enzymes involved in mycobacterial galactan assembly, and studies with these compounds may ultimately facilitate the future development of new therapeutic agents against tuberculosis.

Fluorosugar Chain Termination Agents as Probes of the Sequence Specificity of a Carbohydrate Polymerase

“…The reported syntheses of Gal f derivatives lack the flexibility we needed. 19–20 Routes to compound 2 are not divergent, low-yielding, and exhibit little selectivity for forming the biologically active alpha anomer. 19 A chemoenzymatic synthesis has been described that affords moderate yields.…”

Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay

“…UGM is essential for Mycobacterium tuberculosis [8] and a virulence factor in A. fumigatus [12]. Its role in virulence and the absence of a UGM homolog in mammals has spurred the search and development of inhibitors against this enzyme [21,22]. Several methods have been used to screen inhibitors of UGMs mainly from bacterial sources [23].…”

Antitubercular Drugs Based on Carbohydrate Derivatives

“…The conversion of uridine 5c-diphosphate galactopyranose (UDP-Galp) ( [98]. Analogous reports on derivatives of the sugar nucleotide UDP-Galf showed prevention in the formation of mycobacterial galactan [101]. In yet another report, the synthesis of a library of transition state analogs was found to inhibit both of the glycosyltransferases MurG and MTB GlfT2 [102].…”