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Compounds defeat malaria at every step

Experimental drugs are first to kill all stages of the parasite’s infection cycle

STAGED SHUTDOWN  Compounds that block a key enzyme in malaria parasites kill the protozoans in all stages of infection, new experiments show. A magnified Plasmodium falciparum parasite taken from a blood sample is shown.

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By striking at a critical enzyme in malaria parasites, researchers can defeat the protozoan in all stages of an infection. Compounds kill even those forms of the parasite that hide in the liver or lie low in the bloodstream.

The new battle plan, published November 27 in Nature, arrives at a time when malaria parasites are becoming increasingly resistant to drugs. Malaria parasites, protozoans in the genus Plasmodium, exist in several distinct life stages within the human body, each of which has different treatment requirements. In the study, scientists could wipe out P. vivax and P. falciparum — the main human-infecting parasites — in lab dishes and clear other strains of the infection in mice.

The team used chemicals called imidazopyrazines to stymie the malaria by disabling an enzyme in the parasite that controls the transport of lipid molecules across membranes. The enzyme, called PI(4)K , is essential  to all life stages of the parasite.

The researchers, led by Elizabeth Winzeler of the University of California, San Diego, are tweaking the potential drugs before testing them in humans.

“Now that we found this enzyme, it creates a path forward,” says Winzeler of the parasite-killing strategy.

Malaria, which spreads via mosquito bites, can be difficult to treat. Many of today’s treatments alleviate symptoms without killing all the parasites, Winzeler explains. Infected people may feel better while taking drugs, but may carry parasites and spread infection. Parasites can also hide in the liver for years before reemerging.

Winzeler and her colleagues had previously found that imidazopyrazines can kill some forms of the malaria parasites, but they didn’t know if the compounds kill all life stages. After confirming that the chemicals could kill the parasites in all blood and liver stages, even the dormant liver variety, the researchers tested the molecules in mice. The imidazopyrazines cured infections and protected mice from new infections.

“This is very exciting,” says malaria researcher Jürgen Bosch of Johns Hopkins University. Even though the researchers may be five to 10 years away from clinical trials, the new tactic of blocking PI(4)K  is a breakthrough that will spur more research on this enzyme, he says. “It’s a very, very good starting point.” 

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