title: Inhibition of galactosyltransferases by a novel class of donor analogues.
abstract: Galactosyltransferases (GalT) are important molecular targets in a range of therapeutic areas, including infection, inflammation, and cancer. GalT inhibitors are therefore sought after as potential lead compounds for drug discovery. We have recently discovered a new class of GalT inhibitors with a novel mode of action. In this publication, we describe a series of analogues which provide insights, for the first time, into SAR for this new mode of GalT inhibition. We also report that a new C-glycoside, designed as a chemically stable analogue of the most potent inhibitor in this series, retains inhibitory activity against a panel of GalTs. Initial results from cellular studies suggest that despite their polarity, these sugar-nucleotides are taken up by HL-60 cells. Results from molecular modeling studies with a representative bacterial GalT provide a rationale for the differences in bioactivity observed in this series. These findings may provide a blueprint for the rational development of new GalT inhibitors with improved potency.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Descroix
authors.forename: Thomas
authors.initials: T
authors.lastname: Pesnot
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: Gehrke
authors.forename: Warren
authors.initials: W
authors.lastname: Wakarchuk
authors.forename: Monica M
authors.initials: MM
authors.lastname: Palcic
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002417:Cattle; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D009345:Neisseria meningitidis / Q000201:enzymology; D013329:Structure-Activity Relationship; D014531:Uridine Diphosphate Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D006027:Glycosides; D014531:Uridine Diphosphate Galactose; D005700:Galactosyltransferases