Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

Malaria parasites are evolutionarily prepared to resist drug attack. Resistance is emerging to even the latest frontline combination therapies, which target the blood stages of the Plasmodium parasite. As an alternative strategy, Antonova-Koch et al. investigated the possibilities of drugs against liver-stage parasites (see the Perspective by Phillips and Goldberg). To do so, they devised a luciferase-reporter drug screen for the rodent parasite Plasmodium berghei. Three rounds of increasingly stringent screening were used. From this regime, several chemotypes that inhibit Plasmodium mitochondrial electron transport were identified. Excitingly, several new scaffolds, with as-yet-unknown modes of action but solely targeting the parasites' liver stages, emerged as promising drug leads for further development. Science, this issue p. eaat9446; see also p. 1112 Malaria remains a devastating disease, affecting 216 million people annually, with 445,000 deaths occurring primarily in children under 5 years old. Malaria treatment relies primarily on drugs that target the disease-causing asexual blood stages (ABS) of Plasmodium parasites, the organisms responsible for human malaria. Whereas travelers may rely on short-term daily chemoprotective drugs, those living in endemic regions require long-term malaria protection such as insecticide-treated nets (ITNs) and vector control. However, ITNs do not fully shield individuals from malaria, may lose potency with time, and can be bulky and difficult to use.