American Chemical Society
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Inhibition of Galactosyltransferases by a Novel Class of Donor Analogues

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journal contribution
posted on 2012-03-08, 00:00 authored by Karine Descroix, Thomas Pesnot, Yayoi Yoshimura, Sebastian S. Gehrke, Warren Wakarchuk, Monica M. Palcic, Gerd K. Wagner
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.


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