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Biological Chemistry

Defeating Diarrhea

June 30, 2008 | APPEARED IN VOLUME 86, ISSUE 26

Forget chugging chalky Kaopectate when your next bout of diarrhea hits. A newly synthesized pyridopyrimidine derivative (shown) may one day be used to halt diarrhea caused by toxin-producing strains of the bacteria Escherichia coli. The novel compound, identified by pharmacologist Ferid Murad and coworkers at the University of Texas Health Science Center, prevents the heat-stable enterotoxin (STa) secreted by E. coli from stimulating the buildup of fluids in the intestine and causing diarrhea. Unlike current therapies, which reduce fluids already accumulated, the bromophenyl-substituted pyridopyrimidine derivative synthesized by Murad's team prevents the accumulation of cyclic guanosine monophosphate (cGMP) and therefore the efflux of fluid into the intestines (Proc. Natl. Acad. Sci. USA 2008, 105, 8440). STa binds to the transmembrane guanylyl cyclase type C receptor in intestinal cells, causing intracellular concentrations of cGMP to spike. The increase in cGMP triggers an influx of sodium ions and water to the intestines, which leads to diarrhea. Murad identified the pyridopyrimidine derivative by screening a library of compounds for ones that prevent accumulation of cGMP. The compound can be synthesized in a one-step condensation reaction and purified by flash chromatography.

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