Team finds new target for malaria drugs and vaccines

Gradient centrifugation
of P falciparum-infected RBCs

An investigation into the inner workings of the malaria parasite has revealed that it survives and proliferates in the human bloodstream thanks, in part, to a chemical the parasite produces internally.

This insight provides a powerful new tool for discovering and designing drugs to treat malaria, researchers say. And it gives scientists a hypothetical new vaccine to test: a weakened version of the parasite.

“It's as if we designed a ticking time bomb inside the parasite that's ready to go off, and, when it does, the parasite dies,” said lead study author Joseph DeRisi, PhD, of University of California in San Francisco.

These findings hinge on the discovery of the apicoplast, an organelle that exists within the malaria parasite. When researchers discovered it 15 years ago, they realized that the apicoplast was unlike anything found normally in the human body. And this suggested that drugs designed to interfere with it might kill the parasite while essentially leaving humans unharmed.

Unfortunately, despite extensive study over the years, scientists could not find a way to target the apicoplast. That is, until now.

Dr DeRisi and his colleagues have found that the sole function of the apicoplast, while the parasite is in the blood, is to produce the chemical isopentenyl pyrophosphate (IPP). And this is a necessary building block the parasite uses to construct a variety of other molecules.

The team discovered this by growing samples of Plasmodium falciparum within red blood cells in vitro. The researchers found that, if they treated the parasites with antibiotic drugs that kill the apicoplast, the parasites would all die. But if the investigators fed the parasites IPP at the same time, the parasites lived but lost the apicoplast completely over time.

This work provides a new tool for probing the basic biology of the Plasmodium parasite, Dr DeRisi said. And it suggests a new way of discovering promising drugs to fight malaria.

That's because, while many previous drug-screening efforts have identified multitudes of compounds that appear to inhibit growth of the parasites, most are without a known target. So this new discovery has provided a simple tool to determine whether any particular drug candidate targets the apicoplast.

In addition, the attenuated form of the parasite provides an intriguing hypothetical vaccine candidate, one that would be relatively cheap to produce, Dr DeRisi said. However, he cautioned, the history of malaria control is filled with failed efforts, and several past vaccines have fallen short. Only time and clinical trials will tell if this is a viable solution to the problem.

“This parasite has clearly evolved to be an immune system escape artist,” Dr DeRisi said. “It's no surprise that the simple approaches have not worked.”

This research appeared online in PLoS Biology on August 30.

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