Selective inhibition of beta-1,4- and alpha-1,3-galactosyltransferases: Donor sugar-nucleotide based approach

A combined rational and library approach was used to identify bisphosphonat es (IC50 = 20 mu M) and galactose type 1-N-iminosugar (IC50 = 45 mu M) as n ovel motifs for selective inhibition of beta-1,4-galactosyltransferase (bet a-1,4-GalT) and alpha-1,3-galactosyltransferase (alpha-1,3-GalT), respectiv ely. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in t heir mechanisms can be utilized to design donor sugar or nucleotide analogu es with inhibitory activities selective for only one of the galactosyltrans ferases. Investigation of beta-1,4-GalT inhibition using UDP-2-deoxy-2-fluo rogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observ ation of metal dependent inhibition of beta-1,4-GalT. These observations an d the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltrans ferase inhibitors. (C) 1999 Elsevier Science Ltd. All rights reserved.