New antimalarial agent shows promise

Anopheles Freeborni Mosquito - CDC

Photo: CDC

A new antimalarial compound (DDD107498) tested on mice and several mosquito species has shown great promise, says a study published today (June 18) in the journal Nature . The agent has all the attributes one would look for in an antimalarial drug — activity extending to multiple lifecycle stages of the malaria parasite. In several mice models of malaria, the compound was found to have “comparable or greater efficacy” than the drugs currently being used.

The compound has already “progressed into advanced non-clinical development, with aim of entering into human clinical trials,” notes the paper.

The results gain prominence as the malaria parasite has developed resistance to many of the antimalarial drugs currently being used, including the potent artemisinin. The compound targets the translocation elongation factor 2 (eEF2), which is essential for protein synthesis.

The novel mode of action and excellent drug-like properties (metabolic stability, excellent pharmacokinetics, good bioavailability) makes the compound fight the parasite even when administered as a single-dose treatment. This has great public health implications. For instance, in the case of mice infected with Plasmodium berghei , a single dose of the compound was found to reduce the parasitaemia by 90 per cent.

Besides fighting the parasite, the drug was found to have activity against both the sexual blood stages that cause the disease and the gametocytes that are responsible for malaria transmission. It also exhibited chemoprotection through action on the liver stage.

The compound was found to have excellent activity against the P. falciparum parasite and against several other drug-resistant strains. It fared far better than the currently used artesunate drug against both P. falciparum and P. vivax .

When a female mosquito infected with P. falciparum feeds on a human, parasites in the sporozoite stage enter the bloodstream and go straight into the liver where they infect the liver cells. In the case of liver schizont stage, the compound was found to be effective even when the compound was introduced after infection with P. berghei liver stage was established.

But when the mice were treated with the compound prior to being infected with P. berghei sporozites, no signs of parasitaemia were found even after 30 days, thus establishing its ability to prevent infection.

Blocking transmission

The parasite erythrocytic form differentiates into the asymptomatic male and female gametocytes within the human host. The mature (stage V) gametocytes are infective to mosquitoes. Once ingested by mosquitoes, the gametocytes differentiate into gametes. But the novel compound inhibited the formation of both male and female gametes thus blocking the transmission of the parasite from humans to mosquitoes.

To further test its power to block transmission, mice were first infected with P. berghei and then treated with the compound before mosquitoes took a direct blood meal. Nearly 91 per cent reduction in mosquitoes was seen at day 10 compared with control mosquitoes.

When the mosquitoes that took a blood meal from infected, drug-treated mice were allowed to feed on uninfected mice, there was an 89.5 per cent reduction in the number of mice that developed blood-stage malaria infection.

In 2013, there were 200 million cases of malaria, and nearly 0.6 million deaths across the world. In the case of India, despite halving the number of malaria deaths per 100,000 during the period 1990-2013, malaria remains a “tremendous health burden.” In 2013, there were about 61 million malaria cases in India and nearly 116,000 deaths.

Published in the Hindu on June 18, 2015