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Stanford Report, May 21, 1997

Finding suggests new strategy against malaria

BY HEATHER ROCK WOODS

Stanford researchers have found an unexpected target site that could be used in efforts to starve or poison the parasites that cause malaria.

"My laboratory's research suggests new approaches to develop drugs to treat malaria," said Kasturi Haldar, an associate professor of microbiology and immunology.

The target is a network of tubular membranes that the parasite assembles to procure nutrients from its environment, Haldar's team reported in the May 16 issue of the journal Science. Haldar's postdoctoral fellow, Sabine Lauer, is the first author on the paper.

The parasite needs to build this nutrient supply system because it infects red blood cells, which don't have the machinery to provide the nutrition required for parasite growth and reproduction.

Approximately 40 percent of the world's population lives at risk of becoming infected by malaria. Every year malaria afflicts 200 to 300 million people and kills more than one million children. The disease continues to spread as the mosquitoes that transmit the parasites - and the parasites themselves - become increasingly resistant to standard measures of control.

"Until an effective vaccine is available, it is important to develop new drugs or new combinations of existing drugs to treat the disease," Haldar said. "The main difficulty in developing such drugs is the lack of well-defined targets in the parasite and a lack of a broad range of compounds that are chemically very different to attack the parasite."

In previous studies, Haldar and Heidi Elmendorf, a former Stanford graduate student, established the existence of the tubular network. Haldar and Lauer then showed that it cannot fully form in the presence of a lipid called PPMP.

The new work demonstrates that nutrients can enter the tubular network and reach the parasite. But in red blood cells treated with PPMP, nutrients are not transported because the network is disrupted.

This suggests a way to starve the parasite, Haldar and Lauer said.

"We can block the delivery of nutrients to the parasite and essentially starve the parasite, although it's a slow death," Lauer said.

Thus PPMP and other compounds that interfere with the formation of the nutrient supply system have potential to become a new class of antimalarial drugs, said Haldar.

Their new research also suggests that an intact network could be exploited to deliver antimalarial drugs directly the parasite. Many potential antimalarial drugs are poisonous analogues of parasite nutrients, Haldar said. Because the analogues are almost identical to normal nutrients, the supply system might be able to transport the poisons as well as the nutrients. For example, the study shows that the tubular network transports 5-fluoroorotate, a toxic version of the nutrient orotic acid.

Lauer and Haldar's co-authors on the Science paper are research assistant Nafisa Ghori, who conducted the electron microscopy studies, and Pradipsinh Rathod of The Catholic University of America.

The work was supported by Burroughs Wellcome Fund awards and National Institutes of Health grants. SR