World Health Organization (WHO) estimates that there are 154-289 million cases of malaria and 610,000-971,000 deaths each year. Malaria is caused by a protozoan parasite, Plasmodium, which is transmitted through the bite of a mosquito. In the absence of an effective vaccine against Malaria, chemotherapy remains the only viable treatment option. However with emerging reports of acquired resistance against antifolates and chloroquine, and more recently artemisinin, there is an urgent need for new drugs and drug targets. The genome of Plasmodium falciparum, the species responsible for most mortality, has been sequenced and is predicted to encode 86-99 kinases. Recent high throughput screening efforts of large compound libraries have identified numerous potent hits, which have chemotypes reminiscent of kinase inhibitors. However, the lack of commercially available robust kinase assays has hindered Plasmodium kinome-directed drug discovery. In this application, we aim to develop assays targeted against the kinases expressed in the asexual stage of the parasite's life-cycle, which is responsible for the pathology associated with the disease. Recent studies have identified 36 kinases expressed in this stage that are critical to the parasite's survival, which will serve as our initial targets. These Plasmodium kinase specific assays, based on a three-hybrid split luciferase system, will be further used for high throughput screening of anti-malarial compound libraries. These efforts are both significant and innovative as the identification of target specific inhibitors will not only provide pharmacophores for furthe drug development but also identify chemical probes for studying kinase biology and signaling pathways.
Malaria is a severe infectious disease that remains on the rise and takes the lives of over 660,000 people every year. No vaccines are currently available to eradicate the disease. Current antimalarial therapies are becoming ineffective due to acquired resistance. New targets for drug development that are being explored constitute malarial kinases. Lack of robust methods for interrogating inhibitors against malarial kinases has deterred the development of kinase-specific drugs. Our application seeks to fill this much needed gap and develop low-cost, sensitive assays against malarial kinases, which will help advance the discovery of new and effective therapies for this deadly disease.
