By returning to traditional screening methods, researchers have identified an effective anti-malarial drug candidate, known as NITD609, which seems to kill the blood stages of the two major malaria parasites when administered orally, just once a day. This discovery is especially timely since researchers in Asia have begun to report a building resistance to artemisinin, the main ingredient in current malaria treatments for about 100 million patients each year.
A team of scientists from around the world used high-throughput screening approaches—as opposed to the more widely-used molecular screening processes—to discover a new class of compounds known as the spiroindolones, which show promise for treating malaria. They report their findings in the 3 September issue of the journal Science.
The left panel shows a red blood cell next to four human malaria parasites (Plasmodium falciparum) capable of invading the human cell. The right panel shows a parasite developing inside an infected cell. Image © Science/AAAS
“We used the traditional whole-cell screening approach, which has fallen out of favor as scientists have concentrated more and more on molecular biology and ‘target-based’ or ‘rational’ drug discovery,” said Elizabeth Winzeler, a co-author of the study. “The problem with newer molecular approaches is that you can get a compound that acts against a protein ‘target’ but it may still not cure the disease. With the traditional screening method, you can find out right away if you are going to kill the bug with your compound.”
The group of researchers was able to identify a particular spiroindolone, NITD609, which can kill both Plasmodium falciparum and Plasmodium vivax malaria pathogens, including a range of drug-resistant strains.
“Our compound attacks the malaria parasite during the blood stages,” said Thierry Diagana, another co-author on the study. “During the liver stage, the patient doesn’t know they’re infected with the parasite. But, once it leaves the liver and enters the blood, that’s when people get sick. So, all therapeutics focus on the blood stages because this is when the person becomes symptomatic. You have to deal with the blood stages immediately, once you make the diagnosis.”
The team did note some resistance to NITD609, however, in strains of P. falciparum with certain mutations on the pfatp4 gene.
“We exposed the parasites to sub-lethal concentrations of the NITD609 compound for periods of 3 to 4 months,” said Winzeler. “Then, we compared the genomes of wild-type parasites to these treated parasites in order to find the mutations that emerged over that period of time.”
In light of their findings, the researchers suggest that NITD609 employs a different mechanism of action from other anti-malarial drugs, such as artemisinin. They report no adverse events or negative side effects triggered by the compound in animal models of the disease—and NITD609 is currently undergoing preclinical evaluations.
“Our compound will probably avoid resistance in the future because it is so completely different, molecularly, from other anti-malarial drugs,” said Diagana. “It could possibly replace or become a substitute for artemisinin in the future.”
“This finding is the result of a lot of different people coming together and collaborating,” said Diagana. “Public and private partnerships, as well as many concerned individuals were able to contribute resources and help to support this research.”
“Researchers were really excited about the compound,” said Winzeler. “It soon became easy to get their help.”