Novartis announced that its scientists have discovered a new target for antimalarial drugs. The research, published in Nature, reports on the discovery of phosphatidylinositol-4 kinase (PfPI4K) as the target of a class of experimental antimalarial drugs called the imidazopyrazines, which has the potential to prevent, block and treat multiple stages of the malaria lifecycle. The research is supported by the Wellcome Trust and Medicines for Malaria Venture.
While current treatments for malaria are mostly effective, there have been reports that the efficacy of artemisinin-derivatives has been compromised in parts of South-East Asia. Moreover, antimalarial therapies are only effective against the acute blood stages of the disease, thus leaving some patients at risk of relapse after initial treatment, especially those infected with P. Vivax.
"Our scientists carried out a large phenotypic screen which, coupled with modern genome analysis and editing tools, constitute a powerful technology platform to discover and validate drug targets for next-generation antimalarial drug discovery," said Martin Seidel, institute director of the Genomics Institute of the Novartis Research Foundation (GNF), in a press release.
They then isolated strains of parasites that had become resistant to the compound class and identified the mutated genes. For one of these genes, PfPI4K, they went on to show through biochemical experiments that imidazopyrazines work through interaction with the ATP-binding pocket of the kinase. They also showed that these compounds are active against blood-stage field isolates of the major human malaria pathogens, P. falciparum and P. vivax, and inhibit liver-stage hypnozoites of a parasite P. cynomolgi, which is closely related to P. vivax.