An international team of scientists, including researchers at Columbia University Medical Center (CUMC), has identified a key metabolic enzyme that common malaria parasites require for survival at each stage of infection in humans. The findings raise the possibility of a new approach to combating malaria, one of the world's deadliest diseases. The study was published today in the online edition of the journal Nature.
"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. "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 other co-first author is Case W. McNamara, PhD, research investigator at the Genomics Institute for the Novartis Research Foundation. The study leaders are Elizabeth A. Winzeler, PhD, professor of pharmacology and drug discovery at University of California San Diego, and Thierry Diagana, head of Novartis Institute for Tropical Diseases in Singapore.
The enzyme - phosphatidylinositol 4-kinase (PI4K) - was found by screening more than a million drug compounds against Plasmodium falciparum, the parasite responsible for the most lethal form of malaria. Using this screen, the researchers found a class of compounds known as imidazopyrazines, which are capable of killing several species of Plasmodium at each stage of the parasites' life cycle in its vertebrate host. Also important, the compounds 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.
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.
Then, using cellular imaging, the CUMC team found that imidazopyrazines interfere with the function of PI4K on the parasite Golgi (the organelle that packages proteins for delivery to other cellular destinations). "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.
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," she said.
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