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Published On: Mon, Dec 2nd, 2013

Enzyme may be the key to combating malaria: Study

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.

Plasmodium falciparum ring forms/CDC

Plasmodium falciparum ring forms/CDC

 

 

 

 

 

 

 

 

The study, “Targeting Plasmodium phosphatidylinositol 4-kinase to eliminate malaria”, was published Nov. 27 in 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 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. Elizabeth Winzeler, professor of pharmacology and drug discovery at University of California San Diego 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.”

Columbia University Medical Center news release

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About the Author

- Writer, Co-Founder and Executive Editor of The Global Dispatch. Robert has been covering news in the areas of health, world news and politics for a variety of online news sources. He is also the Editor-in-Chief of the website, Outbreak News Today and hosts the podcast, Outbreak News Interviews on iTunes, Stitcher and Spotify Robert is politically Independent and a born again Christian Follow @bactiman63

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