Disaccharide analogs as probes for glycosyltransferases in Mycobacterium tuberculosis

Glycosyltransferases (GTs) play a crucial role in mycobacterial cell wall biosynthesis and are necessary for the survival of mycobacteria. Hence, these enzymes are potential new drug targets for the treatment of tuberculosis (TB), especially multiple drug-resistant TB (MDR-TB). Herein, we report the efficient syntheses of Araf(α 1 → 5)Araf, Galf(β 1 → 5)Galf, and Galf(β 1 → 6)Galf disaccharides possessing a 5-N,N-dimethylaminonaphthalene-1-sulfonamidoethyl (dansyl) unit that were prepared as fluorescent disaccharide acceptors for arabinosyl- and galactosyl-transferases, respectively. Such analogs may offer advantages relative to radiolabeled acceptors or donors for studying the enzymes and for assay development and compound screening. Additionally, analogs possessing a 5-azidonaphthalene-1-sulfonamidoethyl unit were prepared as photoaffinity probes for their potential utility in studying active site labeling of the GTs (arabinosyl and galactosyl) in Mycobacterium tuberculosis (MTB). Beyond their preparation, initial biological testing and kinetic analysis of these disaccharides as acceptors toward glycosyltransferases are also presented.

The preparation and preliminary screening data are reported for several fluorescent or pro-fluorescent arabinofuranose and galactofuranose disaccharides as probes and substrates for new assays of arabinosyl- and galactosyltransferases of Mycobacterium tuberculosis.Figure optionsDownload as PowerPoint slide