Targeting The Malaria Kinome: Discovering Kinase Inhibitors As Novel Antimalarial Agents

Malaria remains a deadly disease, with over two million deaths reported each year. Mortality, morbidity, and economical burden associated with malaria are predicted to escalate due to the establishment of drug resistance throughout malaria endemic regions of the world. Drug resistance has undermined current antimalarial therapeutics and therefore a dire need for novel antimalarial agents is warranted. Protein kinases have been targeted successfully for cancer chemotherapy, cardiovascular disease, and neurological disorders. A wealth of information from these efforts may be applied to develop novel antimalarial agents. The development of kinase inhibitors as antimalarial drugs is a promising approach because many malarial kinases are essential for the developmental growth of the parasite and these inhibitors may provide chemotypes that are foreign to the parasite. Although protein kinase families are highly conserved, unique structural characteristics and regulatory mechanisms provide opportunities to develop specificity into a malarial kinase drug. A growing amount of evidence has demonstrated inhibitor selectivity differences among malarial kinases and their mammalian homologs. Malarial kinases are under investigation to gain a better understanding of their regulatory role in controlling parasite metabolism and cell cycle control. This understanding should reveal unique differences and perhaps similarities that can then be exploited for drug discovery. The use of drug combinations to combat infectious disease has gained popularity due to the increase in drug resistance. A current recommendation by the World Health Organization strongly suggests that any new antimarial drug destined for public use should be deployed in the form of a drug combination. Interestingly, there has been a paradigm shift in the development of kinase inhibitors for therapeutic indications. Traditional thinking that an inhibitor must be specific for a single kinase has been overturned. Evidence now suggests that the most successful drug candidates are those that target multiple kinases relevant to a particular disease. Simultaneous inhibition of multiple malarial kinases may prove extremely efficacious and circumvent the problems associated with the evolution of rapid rates of drug resistance.