Potential Malaria Drug Stops Parasite Early
One of the top mosquito carriers of malaria, Anopheles gambiae gets its blood meal.
Credit: Jim Gathany, CDC.

Malaria parasites may be stopped in their tracks by a promising new group of compounds, suggests a new study in mice. The compounds may someday yield a new dual-action drug that targets both malaria parasites living in the blood and those hibernating in the liver, the researchers say.

Scientists have known malaria parasites first enter the liver, where they must develop before heading out into the bloodstream to wreak havoc (causing malaria symptoms).

But until now, most anti-malaria drugs have targeted the bloodstream stage, with many of these becoming less effective as the parasites evolve resistance to them, and the few that target the liver stage have notable side effects, according to the researchers.

In the new study, the international team of scientists discovered that compounds called imidazolopiperazines appear to kill the parasites as they develop in the livers of mice.

However, "we have no data on whether the compounds will work on dormant [parasites] in humans," said Elizabeth Winzeler, a researcher at The Scripps Research Institute in La Jolla, Calif., and lead author of the new study. "At this point and we can only infer from animal models."

The researchers posted their data online, including which compounds were active against the liver-stage parasites and which were not, so that interested scientists can use the information. "Hopefully this will be the starting point for new antimalarial drugs," Winzeler said.

A recurring problem

Malaria is caused by a parasite and transmitted through the saliva of a mosquito. The species Plasmodium falciparum and Plasmodium vivax cause the most malaria infections in humans, with P. falciparum, prevalent in sub-Saharan Africa, being the deadliest.

When a malaria-carrying mosquito bites a person, immature forms of the parasite find their way through the bloodstream to the liver. There, they incubate and multiply before reentering the bloodstream to infect red blood cells. In the bloodstream, the parasites grow and multiply until the blood cells burst, pouring toxins into the bloodstream and causing a range of symptoms, including fever, chills and convulsions. Serious cases can lead to kidney failure, coma and death. In 2009, malaria killed nearly 800,000 people, mostly among children in Africa, according to the World Health Organization.

“Almost all of the drugs that have been effective against malaria have been rendered useless due to the evolution of resistances,” said Greg Crowther, a malaria researcher at the University of Washington, who was not involved in the current study. There is one class of antimalarial medications remains effective, “but there are already whispers of resistance starting to evolve with these therapies,” Crowther said. ['Superdrug' Could Fight HIV & Malaria]

In temperate regions such as the U.S., P. vivax poses an additional problem for people apparently cured of the disease: reinfection. After the parasitesenter the liver, they can lie dormant for months or even years before waking up to repopulate the blood. This is one reason why a drug that targets the liver stage of the parasite would be especially useful.

To find new drugs that fight both the blood and liver stages of malaria, Winzeler and her colleagues screened 5,697 compounds known to be effective against P. falciparum in the blood. They removed parasites from the livers of mice and added them to human liver cells in dishes, and tested their compounds to see which could stop the parasites' development.

They found that about 20 percent of the compounds worked, with imidazolopiperazines being the most effective. The researchers then created imidazolopiperazine derivatives that were suitable for animal testing. When they infected mice with malaria parasites, and treated them with these compounds at the same time, the mice did not develop malaria symptoms, even after several weeks.

"Compounds of the [imidazolopiperazine] class appear to actually kill the parasite," Winzeler said.

The next big push forward

Winzeler noted that she and her colleagues still have to figure out how the compounds kill the liver-stage parasites, and how effective they are in humans.

Crowther says that the research is but a "single step on a fairly long path" toward eliminating P. vivax the dormant parasites in the liver. Even so, the study seems like the next big push forward in the malaria research field, he said, adding that many researchers have been talking about focusing on the non-blood stages of malaria.

"Malaria is a really tricky, ubiquitous disease, and as many of the leaders in the field are telling us, it's going to take a multi-pronged effort to get it under control and eradicated," Crowther said. "Bed nets, vaccines, new drugs that target different parasite stages — all of these things are going to be helpful in containing malaria."

The study was published online today (Nov. 17) in the journal Science. The research was partly funded by the pharmaceutical company Novartis.