UK MRC: Target for malaria drugs

Research lead

The UK Medical Research Council (MRC) and its technology transfer arm, MRC Technology (MRCT), said scientists at the MRC’s National Institute for Medical Research working with the MRCT’s Drug Discovery Group have produced a breakthrough in understanding how the malaria parasite triggers its release from infected red blood cells.

The identification of a parasite enzyme that plays a key role in this process has led to the discovery of a lead compound that inhibits the enzyme.

Malaria threatens the lives of hundreds of millions of people and causes around 3 million deaths each year, mostly among young children in the developing world. The most virulent form of the disease is caused by a single-celled parasite called Plasmodium falciparum, which is transmitted by mosquitoes. The parasite invades red blood cells and multiplies until the daughter parasites, known as merozoites, are mature.

For the disease to progress, these merozoites have to escape the now-exhausted cell and re-invade fresh red cells to repeat the cycle. Little is known about how merozoites rupture the old red cell and escape.

The team has discovered that merozoites contain a set of previously unrecognised organelles, termed exonemes, which are involved in escape from the red blood cell. Exonemes contain a proteolytic enzyme, or protease, called PfSUB1, which is essential for long-term survival of the parasite.

When the merozoites are mature and ready to emerge, they discharge PfSUB1 from the exonemes to trigger a series of proteolytic processing events that result in release of infectious parasites.

The team has identified a small molecule compound that inhibits PfSUB1 and prevents merozoite release.

Mike Blackman from NIMR’s Division of Parasitology said, “Malaria parasites are becoming increasingly resistant to conventional drug therapy, and there is an urgent need to develop new treatments based on an in-depth understanding of the biology of the parasite.”

“Our work has shown that PfSUB1 plays a critical role in regulating release of invasive merozoites. We also now know that PfSUB1 is a druggable parasite target.”