The enzyme is vital for the growth and development of multiple species of the Plasmodium parasites that cause malaria and is required at all stages in the parasite life cycle. It is the first chemically validated drug target that is active at all stages in the parasite life cycle, laying the foundations for the development of next-generation antimalarial drugs.
To eliminate malaria, medicines need to be effective against the dormant liver-stage infection that can cause relapses, as well as the symptomatic blood stage, and should also block transmission of the parasite to mosquitoes that spread the disease.
The imidazopyrazines are a new class of experimental antimalarial drugs that are being developed by scientists at Novartis with support from the Wellcome Trust and the Medicines for Malaria Venture. They have potent preventive, therapeutic and transmission-blocking activity in animal models of malaria and are also effective against two species of malaria parasite taken from patient samples. However, until now, the target of this class of experimental drugs was not known.
To investigate this, the international team created parasite strains in the laboratory that are resistant to treatment with the imidazopyrazines and then used genetic sequencing to identify the genes that are mutated to confer resistance. In all cases, the mutation occurred in the gene for PI4K, an enzyme involved in fatty acid metabolism that is active across all stages in the parasite life cycle.
Thierry Diagana, Head of the Novartis Institute for Tropical Diseases, said: “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.”
Dr Richard Seabrook, Head of Business Development at the Wellcome Trust, said: “With growing resistance to existing therapies, we urgently need new malaria medicines to combat the spread of this deadly disease. This discovery is particularly exciting as it identifies a druggable target that is effective in multiple species of the malaria parasite and at all stages of the parasite life cycle, features that are considered vital for a treatment capable of eliminating malaria.”
The imidazopyrazine compounds used in this study may serve primarily as tools for understanding more about the biology of the malaria life cycle; however, the authors suggest that further optimisation could lead to clinical candidates with desirable drug-like characteristics.
Malaria kills more than 660 000 people each year, most of whom are African children. Although current therapies are effective against the most common forms of malaria, these therapies are only effective against the acute blood stages of the disease, leaving some patients at risk of relapse after initial treatment.
There is currently only one licensed drug capable of eliminating the liver stages of malaria infection, but side-effects and weak activity against the blood stages preclude its widespread use. In addition, there is increasing evidence that the efficacy of front-line treatments, the artemisinin derivatives, has been compromised in parts of South-east Asia owing to rising drug-resistant strains of malaria parasites.
Image: Malaria sporozoite on liver. Credit: Volker Brinkmann.
McNamara CW et al. Targeting Plasmodium PI(4)K to eliminate malaria. Nature 2013 (epub ahead of print).