Imidazopyrazines Kill the Malaria Parasite at Every Stage of Its Life Cycle

An enzyme that is vital to all life stages of several species of malaria parasites has been cited as a tempting target for drug developers.

Achieving the goal of malaria elimination will depend on targeting pathways essential across all life stages of the parasite, Plasmodium. Towards this end, investigators at Columbia University Medical Center (New York, NY, USA) collaborated with an international team of researchers to screen more than a million drug compounds against the most lethal malaria parasite, Plasmodium falciparum, in order to identify compounds capable of killing the parasite at each stage of its life cycle.

They reported in the November 27, 2013, online edition of the journal Nature that the class of compounds called imidazopyrazines was capable of inhibiting the intracellular development of P. falciparum and several other species including P. vivax and P. cynomolgi at every stage of infection in the vertebrate host.

Imidazopyrazines demonstrated potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models and were active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax. In addition, they inhibited liver-stage hypnozoites in the simian parasite P. cynomolgi.

The target of imidazopyrazine inhibition was found to be the enzyme phosphatidylinositol 4-kinase (PI(4)K). Imidazopyrazines altered the intracellular distribution of phosphatidylinositol-4-phosphate in the parasite's Golgi organelle by occupying PI(4)K's ATP-binding pocket.

“We think that disrupting the function of PI(4)K at the Golgi stops the parasite from making new membranes around its daughter cells, thereby preventing the organism from reproducing,” said senior author Dr. Marcus C. S. Lee, associate research scientist in microbiology and immunology at Columbia University Medical Center.

“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 Dr. Lee. “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.”

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