Antimalarial drugs have thus far been mainly derived from natural products and synthetic ‘drug-like’ compounds. This study describes the discovery, following screens against libraries of compounds reminiscent of natural products, of promising small molecules that are highly active against the malaria parasite. Of particular interest is a series of bicyclic azetidines that inhibit a novel malaria target, phenylalanine tRNA–ligase. The bicyclic azetidines can cure mice from all life stages of the Plasmodium parasite with a single low-dose in different mouse infection assays, including a humanized mouse model of malaria liver-stage disease. These compounds have the potential to cure and prevent transmission of the disease in a single oral exposure.
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