Malaria is an unrelenting scourge of the developing world, killing 500,000 people per year, most of them children.

Now a group of Swiss scientists say they have found the “Achilles heel” of the Plasmodium falciparum parasite, right at the molecular level.

A protease inhibitor blocks two key enzymes, preventing the germ from infiltrating and invading healthy cells, they write today in Science.

“Plasmodium has a very complex life cycle and encounters different host cells, whether in the blood, liver or even in the mosquito gut,” said Volker Heussler, of the University of Bern, one of the authors. “Strikingly it uses the same two aspartic proteases at each of these steps.”

In a related study, also published in the same magazine, an international team of scientists used CRISPR-Cas9 editing to create particular lines of digestive vacuole plasmepsins IX to X (PMIX and PMX). The first was found to puncture plasma membranes of host cells and in the exit from cells, and the second is key in invading and making use of the cells.

The Swiss scientists then took a plan of attack at this crucial molecular link.

“By taking a closer look at aspartic proteases we have discovered that two of these enzymes are critical for the parasite invasion and egress from infected host cells,” said Dominique Soldati-Favre, the lead author, a microbiologist at the University of Geneva.

The scientists assessed existing protease inhibitors – a group of treatments that had been abandoned since they were considered to have limited application. One of them is known as hydroxyl-ethyl-amine-based scaffold compound 49c.

But in mouse models, the substance with the considerable appellation showed immediate promise against the target enzymes, explained Soldati-Favre, in a school statement.

“We could not select parasites resistant to the inhibitor, meaning that we might circumvent one of the greatest challenges in the fight against malaria,” she stated. “Indeed, since this inhibitor blocks two enzymes rather than just one, the probability that both will develop resistance at the same time is statistically extremely low.”

The Swiss part of the work was supported by the Carigest Foundation, the Swiss National Science Foundation, and a pharmaceutical company named Actelion.

Other scientists are taking alternative approaches at beating back malaria. For instance, it was reported in January in the journal Science Translational Medicine that a genetically-engineered form of Plasmodium could function as an attenuated vaccine.