Each year, malaria parasites infect nearly 500 million people, and cause around 2 million deaths. With resistance to current treatments such as chloroquine becoming increasingly widespread, new approaches are urgently needed. Writing in the February 15 issue of Science, Wengelnik et al. describe the effects of a new type of antimalarial compound, which potently inhibits the synthesis of membranes containing phosphatidylcholine, an activity that is vital when the parasite is developing within infected red blood cells, but which is absent from non-infected cells.

The compound that was analysed, named G25, was identified in previous studies on a series of compounds designed to disrupt phosphatidylcholine biosynthesis by mimicking choline, which showed that in vitro antimalarial activity correlated closely with specific inhibition of phosphatidylcholine biosynthesis. In the present study, G25 was found to potently inhibit the in vitro growth of the most common malaria parasite — Plasmodium falciparum — including strains resistant to current drugs, and was 1,000-fold less toxic to mammalian cells. Encouraged by these observations, Wengelnik et al. assessed the in vivo activity of G25 in monkeys infected with P. falciparum, and found that it could cure infections at doses about 30-fold lower than those that cause toxicity. The doses were also far lower than those used for current therapies, which often cause nausea. Similar curative effects were observed in a different species of monkey infected with P. cynomolgi, a primate parasite closely related to the other main human malaria parasite, P. vivax.

To clarify the mechanism of action of G25, the authors studied the interaction of a radiolabelled analogue of G25 with blood cells. The analogue specifically accumulated in infected blood cells at levels several-hundred-fold higher than in the surrounding medium. In combination with further analysis of lysed cells, this led the authors to suggest that G25 accumulates at the parasite surface in association with the extensive membrane network around the parasite, where it might interfere with choline uptake and thereby inhibit phosphatidylcholine biosynthesis.

Much further testing is needed before the drug could be used for human studies. Also, G25 needs to be injected, although preliminary experiments have identified analogues with the oral bioavailability necessary for the ultimate goal of a pill form that could be used prophylactically, like chloroquine.