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: Karine Descroix, Thomas Pesnot, Yayoi Yoshimura, Sebastian S Gehrke, Warren Wakarchuk, Monica M Palcic, Gerd K Wagner
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 5 Pg. 2015-24 (Mar 08 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22356319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Glycosides
• Uridine Diphosphate Galactose
• Galactosyltransferases

Topics

• Animals
• Bacterial Proteins (antagonists & inhibitors, chemistry)
• Cattle
• Galactosyltransferases (antagonists & inhibitors, chemistry)
• Glycosides (chemical synthesis, chemistry)
• HL-60 Cells
• Humans
• Models, Molecular
• Neisseria meningitidis (enzymology)
• Structure-Activity Relationship
• Uridine Diphosphate Galactose (analogs & derivatives, chemical synthesis, chemistry)