Selective inhibition of β-1,4- and α-1,3-galactosyltransferases: donor sugar-nucleotide based approach Original Research Article

A combined rational and library approach was used to identify bisphosphonates (IC50=20 μM) and galactose type 1-N-iminosugar (IC50=45 μM) as novel motifs for selective inhibition of β-1,4-galactosyltransferase (β-1,4-GalT) and α-1,3-galactosyltransferase (α-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of β-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of β-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors. ©