BackMeddling with malaria
Discovered, discarded more than 50 years ago, an old drug serves as chemical inspiration for a new breakthrough
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In 1934, Adolf Hitler declared himself Führer of Germany and set the stage for the bloodiest war the world has ever seen. The same year, a prolific German scientist called Johann “Hans" Andersag created the first effective chemical weapon in a battle that has claimed many more lives than World War II, a battle that becomes more intense each year.
Andersag and his team at the pharma giant Bayer created chloroquine (then called Resochin), for decades the primary drug against malaria, now the world’s second-deadliest disease after tuberculosis. Malaria kills anywhere from a million to 2.5 million people annually, mainly children and pregnant women. Global warming and resistance to known drugs threatens to make malaria a greater threat than ever.
While chloroquine later made Andersag famous—it was not developed for more than a decade because it was believed to be too potent for human use—he also created a lesser known chemical compound, Endochin. Now, 65 years after formulation, Endochin is the chemical inspiration for a promising new front against malaria.
On Wednesday, a team of scientists spread across 16 institutions in seven countries, reported in Science Translational Medicine the development of an Endochin-derived drug called ELQ-300, which they say is be 30 times more effective in treating malaria than atovaquone, a prominent drug with relatively mild side-effects. At doses 10 times lower than typically used, ELQ-300 completely protected mice from malaria caused by Plasmodium falciparum, a parasite that lives in the gut of the female Anopheles mosquito and passes on to humans when she bites. Plasmodium falciparum is the deadliest of five species of parasite that cause human malaria, accounting for nine of 10 deaths.
Plasmodium parasites are now resistant to multiple drugs, and there is a great, global quest under way to develop a replacement to chloroquine, the cheapest—and for decades—the most effective drug against malaria. Resistance is also developing to the next great hope, artemisinin, developed from a Chinese herbal medicine extracted from a wormwood plant. Scientists speculate it is a matter of time before artemisinin, too, is overwhelmed by the clever little parasite.
The trickiness of the Plasmodium falciparum parasite is particularly evident in the largely failed efforts since the 1970s to develop a vaccine against malaria.
“Even today it (a vaccine) remains out of reach, and for this reason healthcare providers must rely on a dwindling arsenal of anti-malarial drugs to treat the disease and combat drug resistance," Mike Riscoe, a molecular microbiologist and principal investigator of the project—put together in 2009 by Medicines for Malaria Venture (MMV), an international non-profit foundation—told me in an email interview.
As it travels from a mosquito’s saliva into the human bloodstream, then enters and exits the liver, the parasite keeps flashing different proteins on its surface, cleverly flummoxing the immune system. As the immune system rushes to combat one protein, the parasite reveals another that the body’s defence has not yet recognized. With about 60 proteins to play with, the parasite is a formidable, mutating foe.
This is why ELQ-300 is so promising. It is a multi-stage drug, which means it is effective during the parasite’s wanderings. It works by disrupting the mitochondria, which typically serve as the energy source in eukaryotic cells, the kind that make up everything from trees to ants to humans—and the malaria parasite. But in Plasmodium falciparum, the mitochondria serve a different primary function. They produce two of four building blocks that create the parasite’s DNA, its genetic blueprint. This was the discovery made by one of the laboratories of the research team, the Center for Molecular Parasitology at the Drexel University College of Medicine in Philadephia, US. They found that ELQ-300 could stop the creation of these DNA building blocks. Without these, the parasite cannot reproduce. Death is the result. “It works like a cyanide pill for the parasite without affecting humans," said Akhil Vaidya, director of the Drexel Center.
ELQ-300 is easy to make—and cheap to produce—and small quantities are effective, especially if it is combined with other drugs to achieve a single-dose curative regime, instead of typical multi-dose regimens, said Riscoe, who expects the first human tests in two years. The drug has to undergo crucial safety tests in animals first, as the researchers stress.
Much could go wrong. The original experience with Endochin is instructive. The drug worked on birds, but human metabolism rendered it harmless. More than half a century later, the MMV team is confident that their Endochin modification, ELQ-300, will have the hardy Plasmodium falciparum in a spot of bother.
“It is also important to keep in mind that we will constantly need to feed the drug development pipeline of anti-malarials for the foreseeable future, just to keep ahead of resistance development, which is sure to arise," said Vaidya. “ELQ-300 is an example of such pipeline priming."
Samar Halarnkar is a Bangalore-based journalist. This is a fortnightly column that explores the cutting edge of science and technology. Comments are welcome at frontiermail@livemint.com. To read Samar Halarnkar’s previous columns, go to www.livemint.com/frontiermail-
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