Abstract
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.
Highlights
Escherichia coli heat-labile enterotoxin (LT)1 is the causative agent of traveler’s diarrhea and is responsible for the death of hundreds of thousands of children each year in developing countries [1, 2]
The discovery of simple and synthesizable small molecules which can effectively compete with GM1-OS for binding to the receptor binding site of LT would be of great value
The results suggest that the proposed pocket is favorable for hydrophobic binding determinants (Fig. 1B) in cholera toxin (CT) as well as in LT
Summary
Escherichia coli heat-labile enterotoxin (LT)1 is the causative agent of traveler’s diarrhea and is responsible for the death of hundreds of thousands of children each year in developing countries [1, 2]. The proposed hydrophobic target region formed by Ile-58 and Lys-34 has never been occupied in any of the other toxin structures complexed to different galactose derivatives [7,8,9].
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