J Biol Chem, Vol. 274, Issue 47, 33469-33473, November 19, 1999

Using a Galactose Library for Exploration of a Novel Hydrophobic Pocket in the Receptor Binding Site of the Escherichia coli Heat-labile Enterotoxin

From the Department of Biological Structure, the Biomolecular Structure Center, and the ^§ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195

The binding of the B subunits of Escherichia coli heat-labile enterotoxin (LT) to epithelial cells lining the intestines is a critical step for the toxin to invade the host. This mechanism suggests that molecules which possess high affinity to the receptor binding site of the toxin would be good leads for the development of therapeutics against LT. The natural receptor for LT is the complex ganglioside GM1, which has galactose as its terminal sugar. A chemical library targeting a novel hydrophobic pocket in the receptor binding site of LT was constructed based on galactose derivatives and screened for high affinity to the receptor binding site of LT. This screening identified compounds that have 2-3 orders of magnitude higher affinity toward the receptor binding site of LT than the parent compound, galactose. The present findings will pave the way for developing simple and easily synthesizable molecules, instead of complex oligosaccharides, as drugs and/or prophylactics against LT-caused disease.