New Antimalarial Compound Raises Hopes of Eradication
By Anette Breindl
Researchers have developed a new drug that fights the malaria parasite at multiple stages in its life cycle, and in both of its hosts the human and the mosquito raising hopes that if the compound makes it through clinical development, it could ultimately hound the parasite out of existence.
The malaria parasites Plasmodium falciparum and Plasmodium vivax sicken 200 million people a year and kill more than a million of those, many of them young children. Those numbers have made the humble mosquito by far the most dangerous killer on the planet, and have earned malaria a spot at the top of the priority list, with tuberculosis and HIV, as a one of the "Big Three" diseases at the top of the World Health Organization's hit list. The parasite, meanwhile, is unimpressed; it has developed resistance to every drug used to treat it.
Malaria's life cycle is a complex one. Humans are infected by the bite of an infected mosquito; initially, the parasite takes up residence in the liver. Actual symptoms of malaria begin when the parasite enters the bloodstream, which is also the stage at which the next mosquito can become infected. In the mosquito, too, the parasite moves from one site to another, beginning its growth in the gut and moving to the salivary gland.
That life cycle is part of what has made getting a handle on malaria complicated. But the new compound, ELQ-300, can attack malaria at multiple stages in its life cycle.
"The drug, if it's taken up in the blood meal by the female mosquito, will kill the developing parasite," co-corresponding author Michael Riscoe, of Oregon Health Sciences University, told BioWorld Today. And it does so not just in the gut, where it initially develops, but also once it is in the salivary gland, ready to be passed on to the next human.
That, in turn, "decreases the number of vectors, and reduces the burden for the next generation of infections," co-corresponding author Roman Manetsch, of the University of South Florida, told BioWorld Today.
The new compound was discovered in an attempt to optimize the drug properties of endochin, an antimalarial discovered more than 70 years ago.
Endochin kills the malaria parasite, but its pharmacological properties made it an unsuitable drug. A few years ago, the Medicines for Malaria Venture a Swiss nonprofit dedicated to the fight against malaria decided to put together a team that might be able to optimize the drug.
That team reported its results in the March 21, 2013, issue of Science Translational Medicine describing a class of compounds, of which the most promising, ELQ-300, was selected as a preclinical compound.
The results of that optimization turned out to have similarities to another antimalarial: atovaquone, one component of the combination antimalarial Malarone (atovaquone/proguanil).
Essentially, Manetsch said, "we made an atovaquone replacement which is cheaper, but has less propensity to induce resistance."
Like atovaquone, the new compound targets the parasite's mitochondrion specifically, the cytochrome bc1 complex without affecting the mitochondria of mammals. ELQ-300, however, appears to bind in a different spot than atovaquone.
Malaria parasites develop rapid resistance to atovaquone when the team grew parasites in the presence of atovaquone, such resistance began to pop up within a month. But with ELQ-300, no resistance became apparent over the entire eight weeks of the experiment. In their paper, the authors noted that given enough time, "drug resistance is inevitable for antimalarial agents."
But the slow pace at which resistance to ELQ-300 appears to develop does suggest that a time window could exist to get rid of malaria before malaria gets rid of its vulnerability to the drug.
Another strength of ELQ-300 is that it is long acting. It has not yet been tested in humans, and its solubility will need to be improved before it is ready for human clinical trials, so how long it will last in the human bloodstream is unclear. But the drug is long lasting in mice, rats and dogs, and its half-life "tends to get longer as you move up the evolutionary ladder," Riscoe said.
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