Malaria Parasite Discovered, Could Help with Treatment of Health Issue

A recent study examines a metabolic enzyme that's common in malaria parasites as a means of survival during the initial stages of human infection. 

"Perhaps the most exciting aspect of our findings is that this enzyme is required at all stages of the parasites' life cycle in humans," said co-first author Marcus C.S. Lee, PhD, associate research scientist in microbiology & immunology at CUMC, via a press release. "This is important because most antimalarials are effective at killing the parasites only as they circulate in the bloodstream. However, the parasites can hide in the liver for years before reemerging and triggering a relapse of the disease. By identifying this enzyme, we may be able to develop a new way to kill the parasites in their dormant stage."

The enzyme, known as phosphatidylinositol 4-kinase (PI4K) is typically found by screening over a million drug compounds against Plasmodium falciparum. This is the parasite that's responsible for the most lethal form of malaria. Researches found via various screens that a class of compounds known as imidazoprazines, which are capable of killing several species at the initial life stage, had no effect on human cells. 

The researchers identified the target of the imidazopyrazines by evolving parasite cell lines that were resistant against the drugs and then analyzing the parasites' genomes for the changes responsible for conferring resistance. Those genetic changes pointed to the gene that encodes PI4K.

By using novel genetic tools to confirm that the PI4K was a direct target of the imidazoprazines, the team found that the imidazopyrazines interfere with the function of PI4K on the parasite Golgi.
The CUMC team, led by David Fidock, PhD, professor of microbiology & immunology and medical sciences (in medicine), used novel genetic tools to confirm that PI4K was being directly targeted by the imidazopyrazines.

"We think that disrupting the function of PI4K at the Golgi stops the parasite from making new membranes around its daughter cells, thereby preventing the organism from reproducing," said Dr. Lee, via the release. "Because PI4K is also found in humans, Dr. Winzeler said, the next challenge is to develop a drug that retains selectivity between the parasite and human versions of the enzyme. "As we now know the identity of this protein and hope to soon solve its structure, this task should be much easier."

More information regarding the study can be found via the journal Nature.