Malaria is still a deadly disease worldwide. According to the U.S. Centers for Disease Control and Prevention (CDC), in 2017 there were about 219 million cases of the disease globally and about 435,000 people died from it, mostly children in the African Region.
Researchers with the Pasteur Institute and CNRS (French National Center for Scientific Research) in France recently identified molecules that can inhibit DNA methylation and kill even the most resistant of the malaria parasites, Plasmodium falciparum. They published their work in the journal ACS Central Science.
The Plasmodium parasites are transmitted to humans via bites from infected mosquitoes. The parasites have an unusual ability to live in two very different hosts because of the plasticity and adaptability of their genome. The investigators studied the epigenetic mechanisms in the plasticity, with a particular focus on DNA methylation. DNA methylation is a type of regulation that occurs when a methyl group—a carbon atom with three hydrogen atoms attached—are added to the DNA molecule. DNA methylation acts as a switch, turning gene expression on or off.
The Plasmodium parasite has a complicated life cycle, able to live in the salivary glands of the mosquito and, when transmitted to humans, moving to the liver and then the blood.
“At each stage in the cycle, epigenetic mechanisms such as histone or DNA modifications regulate the expression of the parasite’s genes, enabling the specific expression of some genes in the cell at a given time so that the parasite can adapt to its environment,” said Flore Nardella, a contract researcher in the Institute Pasteur’s Biology of Host-Parasite Interactions laboratory.
Last year, CNRS researcher Artur Scherf, who runs the laboratory Nardella works in, showed the importance of epigenetic DNA changes in the Plasmodium life cycle. So the two groups decided to partner on identifying molecules that could inhibit DNA methylation.
“Artur’s team had a thorough knowledge of the epigenetic mechanisms in malaria, and we had an original chemical library with inhibitors that had already been optimized for these modifications,” said Paola B. Arimondo, a chemist, CNRS Director of Research and Head of the Epigenetic Chemical Biology Unit.
They focused on Plasmodium falciparum strains that were artemisinin resistant. The parasites were allowed to infect human red blood cells. They then tested more than 70 methylation-inhibiting molecules on the parasites.
“As soon as we tested the first molecules, we saw significant activity, comparable with drugs such as chloroquine,” Nardella said. “That’s very rare when testing a new library of molecules.”
Some of the drugs killed the parasites in the blood in only six hours. In a second series of experiments, the most effective drugs were tested on resistant strains and again, the molecules were effective in killing the malaria parasites.
“This study shows, for the first time, that parasites in the blood, including artemisinin-resistant strains, can be killed rapidly by targeting DNA methylation,” said Arimondo.
“Given the treatment failure observed in South-East Asia in particular, it is important to find new therapeutic targets,” added Nardella. “Methylation could pave the way for new drugs that, combined with artemisinin, could eliminate resistant parasites.”
They continued their research in laboratory animals, and the treatments were effective as well. The next approach will be to optimize the most promising drugs and identify ones that may act on other stages of the parasites.