Antimalarial drug discovery — approaches and progress towards new medicines

Key Points Although malaria continues to affect 40% of the world's population and is estimated to be responsible for up to 1 million deaths per year, the number of cases reported by the World Health Organization has declined. Some fear that these advances will be reversed if parasites become resistant to artemisinins, which is currently the only class of antimalarial drug that works effectively against all drug-resistant parasite strains. Ever-slowing response times to artemisinin monotherapies and the risk that these compounds will lose effectiveness over time has spurred the new search for replacement therapies. The World Health Organization and several non-profit, non-governmental organizations have made the elimination of malaria a long-term public health goal. This has generated interest in developing novel antimalarial compounds that can not only eliminate the symptoms of malaria but also remove all parasites from the body and prevent the spread of malaria. In recent years, sophisticated and powerful cellular and phenotypic screening methods have identified drug candidates that are active against different stages of the parasite's life cycle, and at least two of these novel classes of antimalarial drugs are being tested for efficacy in humans. For known, validated antimalarial 'targets', structure-guided drug design has yielded drug candidates that have higher potency and activity against drug-resistant malaria parasites than the drugs that are currently available against these targets. Insightful chemical design has also resulted in new drug candidates that have improved potency or that remain in the patient's bloodstream for a longer period of time. Current antimalarial therapy heavily relies on artemisinins, a drug class that only targets the blood stages of the parasite and which is increasingly feared to elicit drug resistance. Flannery, Chatterjee and Winzeler discuss the approaches used to develop novel drugs that are active against different life cycle stages with the ultimate aim of eliminating malaria. Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public–private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of th