Team discovers why drug fails to kill flatworm species
New derivatives of compound being developed to treat parasitic infections
Scientists at The University of Texas Health Science Center, now called UT Health San Antonio, have discovered why oxamniquine, a drug used to treat a global infection called schistosomiasis, is only effective against one species of the parasitic flatworm and not two others.
Improving oxamniquine therapy in schistosomiasis is an important issue worldwide. More than a quarter of a billion people are infected with three major species of the parasites, and health care workers are relying on a single drug, called praziquantel, to treat the three.
Schistosome infections are contracted through contaminated water and the reinfection rate is high. Leaders fear that resistance to praziquantel will develop and become a global problem. Combination therapy using drugs that have different modes of action, namely oxamniquine derivatives and praziquantel, could mitigate the threat.
The new research by UT Health San Antonio was featured July 7 in the Journal of Biological Chemistry, which devoted its cover to the group’s latest study.
Oxamniquine binds very well to a pocket of the sulfotransferase enzyme of Schistosome mansoni, which is 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 and S. japonicum species of the flatworm. S. haematobium is present in Africa and the Middle East, and S. japonicum is in China, Taiwan, the Philippines and Southeast Asia.
“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 senior author Philip LoVerde, Ph.D., professor of biochemistry and structural biology in the Joe R. & Teresa Lozano Long School of Medicine at UT Health.
“Because our colleagues have resolved the crystal 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,” Dr. LoVerde said.
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. Dr. Taylor is a senior research scientist with the X-ray Crystallography Core Laboratory in the Department of Biochemistry and Structural Biology, Long School of Medicine.
“We have enzymes that do the same job, but our enzymes apparently don’t covert 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.
An analogy offers insight into why oxamniquine fails to kill S. haematobium and S. japonicum.
In the game of baseball, players wear gloves that have a pocket to catch the ball. When the players stretch open their hand, the glove opens, creating room for the ball to land securely in the sweet spot, the pocket. Once the ball is caught, the players close their hand to secure it.
If the glove is brand new and not yet conditioned, it is still rigid. In that condition, even though a player stretches open his hand, the glove does not open enough for the incoming ball to reach the pocket. The result is a dropped ball.
The rigid glove not opening to catch the ball is a picture of the disconnection between oxamniquine (the incoming ball) and the enzyme pockets of S. haematobium and S. japonicum.
This work is supported by the National Institute of Allergy and Infectious Diseases and the Welch Foundation. Additional support is from the UT Health Cancer Center and the Office of the Vice President for Research at UT Health San Antonio.