Schistosomiasis, also called snail fever, is an infection of the larval worms of freshwater snails. More than a quarter of a billion people are infected with three major species of the parasites.
Health care workers rely on a single drug, called praziquantel, to treat the three, but as its use increases, the parasite’s resistance also increases.
Schistosome infections are contracted through contaminated water, and the reinfection rate is high. Scientists fear that resistance to praziquantel will become a global problem.
They have turned to another drug, called oxamniquine, which binds well to a pocket of the sulfotransferase enzyme of Schistosome mansoni, endemic to Brazil, the Caribbean and Africa. This enzyme converts the drug into a toxic byproduct that attacks the parasite, the researchers reported.
At the same time, the drug does not bind as effectively to the same enzyme pockets of the S. haematobium species of the flatworm, present in Africa and the Middle East, nor the S. japonicum species of the flatworm, found in China, Taiwan, the Philippines and Southeast Asia.
Combination therapy using drugs that have different modes of action, namely oxamniquine derivatives and praziquantel, could mitigate the threat.
“We’ve learned that the reason oxamniquine doesn’t work well enough to kill those species is that it doesn’t fit into the binding pocket properly,” said Philip LoVerde, Ph.D., professor of biochemistry and structural biology and senior author of a study that was featured in the Journal of Biological Chemistry.
“Because our colleagues have resolved the crystaline structures of these enzymes in each species, we are able to make derivatives of oxamniquine that, in fact, do fit in the binding pocket and do kill each species.”
The new derivatives are being made in the Center for Innovative Drug Discovery, a collaboration of UT Health San Antonio and The University of Texas at San Antonio.
Humans have sulfotransferase enzymes just like the parasites do, said Alex Taylor, Ph.D., lead author of the journal article and senior research scientist with the X-ray Crystallography Core Laboratory at UT Health San Antonio.
“We have enzymes that do the same job, but our enzymes apparently don’t convert this drug in the same way the parasite’s does. The parasite’s system converts this drug into something toxic that kills it. Our system does not,” Dr. Taylor said.