Researchers have identified the protein in malaria-causing Plasmodium parasites that is inhibited by a newly discovered class of anti-malarial compounds known as imidazopyrazines. The protein, phosphatidylinositol 4-kinase (PI4K), is the first potential malaria drug target shown to be essential to all stages of the Plasmodium life cycle; imidazopyrazines impede its activity throughout this process. Led by Elizabeth Winzeler, Ph.D., of the University of California, San Diego and Novartis Research Foundation, the research was published online today in Nature. The work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and other organizations.
When a Plasmodium-carrying mosquito bites a human, it transmits infectious parasites that travel to the liver, where they multiply and mature, and then spread throughout the bloodstream, causing malaria symptoms to develop. Dr. Winzeler and her colleagues administered imidazopyrazines to mice and nonhuman primates infected with Plasmodium and found that the compounds blocked the parasites’ development both in the liver and in the bloodstream stages of infection. They also exposed Plasmodium parasites directly to imidazopyrazines and searched for genetic differences between parasites susceptible to the compounds and those that were resistant. They found that the imidazopyrazine-resistant parasites had mutated versions of the gene that codes for PI4K.
Currently, only one drug, primaquine, has been approved for elimination of liver-stage parasites for the treatment of relapsing malaria. Knowing that PI4K makes Plasmodium parasites susceptible to imidazopyrazines during the liver and bloodstream stages should help researchers optimize these compounds for future clinical testing in humans, the study authors write.