Novel Antimalarial Agent Has New Mode Of Action

A new chemical agent effective against a malaria parasite at multiple life stages has joined the ranks of potential new treatments. Researchers at the University of Dundee, in Scotland, have discovered a quinoline diamine that blocks protein translation in Plasmodium falciparum, a malaria parasite, and eventually kills the organism (Nature 2015, DOI: 10.1038/nature14451).

Antimalarial drugs typically interfere with only one stage of the parasite’s life cycle. But the new compound, called DDD107498, may not only treat malaria patients but also protect people from acquiring the disease and prevent carriers from spreading it.

To discover the new compound, the researchers screened a library of more than 4,700 small molecules. Then they chemically optimized their best hit, increasing its potency 120-fold. When given to mice infected with malaria, a single dose of the agent decreased the presence of parasites in their blood by 90%.

Because DDD107498 has a long half-life in the blood—16 to 19 hours in mouse models—the researchers estimate that it could be an inexpensive malaria treatment: perhaps as little as $1.00 per dose. This would especially benefit the large number of malaria patients who live in extreme poverty.

The team, led by Kevin D. Read and Ian H. Gilbert, identified the compound’s target as a protein translation factor, dubbed PfeEF2. When PfeEF2 is inhibited, parasites cannot synthesize essential proteins and they die. Unlike many other potential treatments in the field, DDD107498 effectively kills the malaria parasite in its gametocyte stage, preventing proliferation and spread beyond the host. Read says the compound is “the most potent transmission blocking agent that has been identified to date.”

“DDD107498 could be the first member of an exciting new class of antimalarial drugs,” says Jonathan Vennerstrom, a medicinal chemist at the University of Nebraska Medical Center who was not involved in the work.

DDD107498 is now undergoing safety trials, Read says, and may enter clinical trials in about a year.