Novartis scientists have discovered a new drug target for treating malaria. The discovery, which is published online in the journal Nature, identifies phosphatidylinositol-4 kinase (PfPI4K) as the target of the imidazopyrazines, a novel experimental antimalarial compound class that inhibits the development of multiple malaria-causing Plasmodium species at each stage of infection in the human host.
The on-going research to develop imidazopyrazines as a new treatment for malaria is supported by the Wellcome Trust and Medicines for Malaria Venture.
Each year malaria kills more than 660,000 people most of whom are African children. While current therapies are effective against the most common forms of malaria, recent publications suggest that the efficacy of the artemisinin-derivatives has been compromised in parts of South-East Asia. In addition, these therapies are only effective against the acute blood stages of the disease, thus leaving some patients at risk of relapse after initial treatment. Relapse prevention is especially important for P. vivax, which can form hypnozoites, dormant parasites that can persist in the liver for up to two years before reinitiating a blood-stage infection.
“This new target for malaria provides an avenue to develop the next-generation antimalarial drugs that are capable of preventing, treating and blocking the spread of malaria, a key goal of Novartis,” commented Thierry Diagana, Head of the Novartis Institute for Tropical Diseases. “Compounds that inhibit this new target have the potential to complement our current malaria drug pipeline, KAE609 and KAF156, and could provide a path toward elimination of the disease.”
The paper describes how scientists discovered a new class of compound with an imidazopyrazine core, to identify this new malaria target. “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).
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.
Scientists from GNF and NITD collaborated with an international team of scientists from the University of California, San Diego, and Columbia University.